Benzamides

ABSTRACT

Novel benzamide derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein W 1 , W 2 , R 1  to R 7 , R 6 , X and Y have the meaning according to the claims, are positive allosteric modulators of the FSH receptor, and can be employed, inter alia, for the treatment of fertility disorders.

PRIORITY CLAIM

This application claims the benefit of U.S. Provisional application Ser.No. 61/508,861, filed on Jul. 18, 2011, and 61/526,342, filed on Aug.23, 2011, which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I)

wherein W¹, W², R¹ to R⁷, R⁶, X and Y have the meaning according to theclaims, and/or physiologically acceptable salts thereof. The compoundsof formulas (I) can be used as positive allosteric modulators of thefollicle stimulating hormone receptor (FSHR). Objects of the inventionare also pharmaceutical compositions comprising the compounds of formula(I), and the use of the compounds of formula (I) for the treatment offertility disorders.

BACKGROUND

Gonadotropins serve important functions in a variety of bodily functionsincluding metabolism, temperature regulation and the reproductiveprocess. Gonadotropins act on specific gonadal cell types to initiateovarian and testicular differentiation and steroidogenesis. Thegonadotropin FSH (follicle stimulating hormone) is released from theanterior pituitary under the influence of gonadotropin-releasing hormoneand estrogens, and from the placenta during pregnancy. FSH is aheterodimeric glycoprotein hormone that shares structural similaritieswith luteinizing hormone (LH) and thyroid stimulating hormone (TSH),both of which are also produced in the pituitary gland, and chorionicgonadotropin (CG), which is produced in the placenta. In the female, FSHplays a pivotal role in the stimulation of follicle development andmaturation and in addition, it is the major hormone regulating secretionof estrogens, whereas LH induces ovulation. In the male, FSH isresponsible for the integrity of the seminiferous tubules and acts onSertoli cells to support gametogenesis.

The hormones are relatively large (28-38 kDa) and are composed of acommon α-subunit non-covalently bound to a distinct 3-subunit thatconfers receptor binding specificity. The cellular receptor for thesehormones is expressed on testicular Sertoli cells and ovarian granulosacells. The FSH receptor is known to be members of the G protein-coupledclass of membrane-bound receptors, which when activated stimulate anincrease in the activity of adenylyl cyclase. This results in anincrease in the level of the intracellular second messenger adenosine3′,5′-monophosphate (cAMP), which in turn causes increased steroidsynthesis and secretion. Hydropathicity plots of the amino acidsequences of these receptors reveal three general domains: a hydrophilicamino-terminal region, considered to be the amino-terminal extracellulardomain; seven hydrophobic segments of membrane-spanning length,considered to be the transmembrane domain; and a carboxy-terminal regionthat contains potential phosphorylation sites (serine, threonine, andtyrosine residues), considered to be the carboxy-terminal intracellularor cytoplasmic domain. The glycoprotein hormone receptor family isdistinguished from other G protein-coupled receptors, such as theβ-2-adrenergic, rhodopsin, and substance K receptors, by the large sizeof the hydrophilic amino-terminal domain, which is involved in hormonebinding.

Annually in the U.S. there are 2.4 million couples experiencinginfertility that are potential candidates for treatment. FSH, eitherextracted from urine or produced by recombinant DNA technology, is aparenterally-administered protein product used by specialists forovulation induction and for controlled ovarial hyperstimulation. Whereasovulation induction is directed at achieving a single follicle toovulate, controlled ovarial hyperstimulation is directed at harvestingmultiple oocytes for use in various in-vitro assisted reproductivetechnologies, e.g. in-vitro fertilization (IVF). FSH is also usedclinically to treat male hypogonadism and male infertility, e.g. sometypes of failure of spermatogenesis.

FSHR is a highly specific target in the ovarian follicle growth processand is exclusively expressed in the ovary. However, the use of FSH islimited by its high cost, lack of oral dosing, and need of extensivemonitoring by specialist physicians. Hence, identification of anon-peptidic small molecule substitute for FSH that could potentially bedeveloped for oral administration is desirable. Low molecular weight FSHmimetics with agonistic properties are disclosed in the internationalapplications WO 2002/09706 and WO 2010/136438 as well as the U.S. Pat.No. 6,653,338. Furthermore, WO 2009/105435 is directed to 3-(amido orsulphamido)-4-(4-substituted-azinyl)-benzamides which are useful as aninhibitor of the chemokine receptor CXCR3, and for preventing ortreating a CXCR3-mediated disease, e.g. inflammation. There is still aneed for low molecular weight hormone mimetics that selectively activateFSHR.

SUMMARY OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been surprisingly found that the compounds according to theinvention and salts thereof have very valuable pharmacologicalproperties while being well tolerated. In particular, they act as FSHRagonists. The invention relates to compounds of formula (I)

wherein

-   W¹, W² denote independently from one another N or CR⁸,    -   with the proviso that at least one of W¹ or W² denotes N;-   R¹ denotes —(CY₂)_(n)-E-(CY₂)_(n)-Het³, —(CY₂)_(n)-Cyc-Het³,    —(CY₂)_(n)—NY-Het³, —(CY₂)_(n)—CONH-Het³, —(CY₂)_(n)—NHCO-Het³,    —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³, —(CY₂)_(n)—NY—Ar,    —(CY₂)_(n)—CONH—Ar, —(CY₂)_(n)—NHCO—Ar,    —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)—Ar, —(CY₂)_(n)-CyC, —(CY₂)_(n)—NY-Cyc,    —(CY₂)_(n)—CONH-Cyc, —(CY₂)_(n)—NHCO-Cyc, —(CY₂)_(n)—NHCO—NH-Cyc, Y,    —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY, —(CY₂)_(n)—SO₂Y,    —(CYR⁸)_(n)—CO—(CY₂)_(n)—N(R⁸)₂,    (CY₂)_(n)—[C(Y)(OH)]_(m)—(CYR⁸)_(n)—NY₂,    [—(CY₂)_(n)—O]—(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCOOY,    —(CY₂)_(n)—NYSO₂Y, —(CY₂)_(n)—NYCON(R⁸)₂, —(CY₂)_(n)—NHCO—CH═CH₂,    —(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂ or —(CY₂)_(n)—CN;-   R² denotes Y;-   R¹, R² together also denote —(CY₂)_(p)—NH—(CY₂)_(p)—,    —(CY₂)_(p)—NHCO—(CY₂)_(p)—, —(CY₂)_(p)—CONH—(CY₂)_(p)—,    —(CY₂)_(p)—N(COA)-(CY₂)_(p)—, —(CY₂)_(p)—N(COOA)-(CY₂)_(p)—,    —(CY₂)_(p)—C(Y)(Het³)-(CY₂)_(p)—,

-   R³ denotes —(CY₂)_(n)-Het¹, —(CY₂)_(n)-Het³, —(CY₂)_(n)—Ar,    —C(Y)(OY)—Ar, Y or —(CY₂)_(n)-Cyc;-   R⁴ denotes Y, COY or SO₂Y;-   R⁵ denotes E-Ar, NY—Ar, Cyc, Y, OY, NYY, NYCOOY, NYCOY, COY, COOY,    SO₂Y, Het¹ or Het³;-   R⁶, R⁷ denote independently from one another H;-   R⁶, R⁷ together also denote —(CY₂)_(p)—;-   R⁸ denotes Y or Ar;-   X, E denote independently from one another —(CY₂)_(m)—, O, CO, —COO—    or SO₂;-   Y denotes H or A;-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7H atoms can be replaced independently from one another by Hal, ═O    and/or OH;-   Cyc denotes cycloalkyl having 3-7 C atoms,    -   in which 1-4H atoms can be replaced independently from one        another by Hal and/or OH;-   Ar denotes an unsaturated or aromatic mono- or bicyclic carbocycle    having 3-10 C atoms,    -   which can be substituted by at least one substituent selected        from the group of A, Hal, —(CY₂)_(n)—OY, COOY, CONH₂, NHCOY,        —(CY₂)_(n)—NYCOOY, —(CY₂)_(n)—NY₂, NO₂, SO₂Y, SO₂NY₂, NYSO₂Y,        —(CY₂)_(n)—CN, —(CY₂)_(n)-Het² and Cyc, or which can be fused to        Cyc;-   Het¹ denotes an unsaturated or aromatic mono- or bicyclic    heterocycle having 1-10 C atoms and 1-4 N, O and/or S atoms,    -   which can be substituted by at least one substituent selected        from the group of Hal, A, Cyc, OY, ═O, COOY, CONH₂, NHCOY,        —(CY₂)_(n)—NY₂, SO₂Y, SO₂NY₂, NHSO₂Y, CN, Ar and        —(CY₂)_(n)-Het³;-   Het² denotes a saturated or unsaturated monocyclic 5- or 6-membered    heterocycle having 1-4 C atoms and 1-4 N, O and/or S atoms, which    can be substituted by A and/or ═O;-   Het³ denotes a saturated mono- or bicyclic heterocycle having 3-7 C    atoms and 1-4 N, O and/or S atoms,    -   which can be substituted by at least one substituent selected        from the group of ═O, A, Hal, —(CY₂)_(n)-Cyc, —(CY₂)_(n)—OY,        COY, COOY, CONY₂, NHCOY, —(CY₂)_(n)—NY₂, CN, SO₂Y and        —(CY₂)_(n)—Ar;-   Hal denotes F, Cl, Br or I;-   m, n denote independently from one another 0, 1, 2, 3, 4, 5 or 6;    and-   p denotes 1, 2 or 3;-   and/or a physiologically acceptable salt thereof,

with the proviso that the following compounds are excluded:

-   3-(3-chloro-benzoylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-4-(4-ethyl-piperazin-1-yl)-benzamide;-   3-(3-chloro-benzoylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-4-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-benzamide;    and-   4-[1,4′]bipiperidinyl-1′-yl-3-(3-chloro-benzoylamino)-N-[2-(4-chloro-phenyl)-ethyl]-benzamide.

In particular, the invention relates to a compound of formula (I)

wherein

-   W¹, W² denote independently from one another N or CH,    -   with the proviso that at least one of W¹ or W² denotes N;-   R¹ denotes —(CY₂)_(n)-E-Het³, —(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)-Het¹,    —(CY₂)_(n)—CONH-Het¹, —(CY₂)_(n)—NHCO-Het¹, —(CY₂)_(n)—Ar,    —(CY₂)_(n)-Cyc, —(CY₂)_(n)—CONH-Cyc, —(CY₂)_(n)—NHCO-Cyc, A,    —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY, —(CY₂)_(n)—SO₂Y, —(CYR⁸)_(n)—CONY₂,    —(CYR⁸)_(n)—NY₂, —(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCOOY,    —(CY₂)_(n)—NYCONY₂ or —(CY₂)_(n)—NHCO—CH═CH₂;-   R¹, R² together also denote —(CY₂)_(p)—NH—(CY₂)_(p)—,    —(CY₂)_(p)—NHCO—(CY₂)_(p)—, —(CY₂)_(p)—CONH—(CY₂)_(p)—,    —(CY₂)_(p)—N(COA)-(CY₂)_(p)—, —(CY₂)_(p)—N(COOA)-(CY₂)_(p)—,

-   R³ denotes —(CY₂)_(n)-Het¹, —(CY₂)_(n)-Het³, —(CY₂)_(n)—Ar, H, A or    —(CY₂)_(n)-Cyc;-   R⁴ denotes Y;-   R⁵ denotes E-Ar, H, A, COOY, SO₂Y, Het¹ or Het³;-   R², R⁶, R⁷ denote independently from one another H;-   R⁶, R⁷ together also denote —(CY₂)_(p)—;-   R⁸ denotes H, A or Ar;-   X, E denote independently from one another —(CY₂)_(m)—, O, CO, —COO—    or SO₂;-   Y denotes H or A;-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7H atoms can be replaced independently from one another by Hal    and/or ═O;-   Cyc denotes cycloalkyl having 3-7 C atoms,    -   in which 1-4H atoms can be replaced independently from one        another by Hal;-   Ar denotes an unsaturated or aromatic mono- or bicyclic carbocycle    having 3-10 C atoms,    -   which can be substituted by at least one substituent selected        from the group of A, Hal, OY, COOY, CONH₂, NHCOY, NY₂, NO₂,        SO₂Y, CN and Het², or which can be fused to Cyc;-   Het¹ denotes an unsaturated or aromatic mono- or bicyclic    heterocycle having 1-10 C atoms and 1-4 N, O and/or S atoms,    -   which can be substituted by at least one substituent selected        from the group of Hal, A, Cyc, OY, COOY, CONH₂, NHCOY, NY₂,        SO₂Y, SO₂NY₂, NHSO₂Y, CN and Ar;-   Het² denotes an unsaturated monocyclic 5-membered heterocycle having    1-3 C atoms and 2-4 N and/or S atoms,    -   which can be substituted by A;-   Het³ denotes a saturated mono- or bicyclic heterocycle having 3-7 C    atoms and 1-4 N, O and/or S atoms,    -   which can be substituted by at least one substituent selected        from the group of ═O, A, Hal, —(CY₂)_(n)-Cyc, —(CY₂)_(n)—OY,        COY, COOY, CONY₂, NHCOY, NY₂, CN, SO₂Y and —(CY₂)_(n)—Ar;-   Hal denotes F, Cl, Br or I;-   m, n denote independently from one another 0, 1, 2, 3, 4, 5 or 6;    and-   p denotes 1, 2 or 3;

and/or physiologically acceptable salts thereof,

with the proviso that the following compounds are excluded:

-   3-(3-chloro-benzoylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-4-(4-ethyl-piperazin-1-yl)-benzamide;-   3-(3-chloro-benzoylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-4-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-benzamide;    and-   4-[1,4′]bipiperidinyl-1′-yl-3-(3-chloro-benzoylamino)-N-[2-(4-chloro-phenyl)-ethyl]-benzamide.

For the sake of clarity, the fusion of Cyc to the carbocycle in the Ardefinition refers to a condensed ring system, wherein another ringsystem is constructed on the mono- or bicyclic carbocycle with theresult of a bi- or tricyclic carbocycle. Moreover, the disclaimer isvalid for any embodiment of the invention described herein ifappropriate.

DETAILED DESCRIPTION OF THE INVENTION

In the meaning of the present invention, the compound is defined toinclude pharmaceutically usable derivatives, solvates, prodrugs,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds. The term “solvates” of the compounds istaken to mean adductions of inert solvent molecules onto the compounds,which are formed owing to their mutual attractive force. Solvates are,for example, mono- or dihydrates or alkoxides. The invention alsocomprises solvates of salts of the compounds according to the invention.The term “prodrug” is taken to mean compounds according to the inventionwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention, as described, for example, in Int. J. Pharm. 115, 61-67(1995). It is likewise possible for the compounds of the invention to bein the form of any desired prodrugs such as, for example, esters,carbonates, carbamates, ureas, amides or phosphates, in which cases theactually biologically active form is released only through metabolism.Any compound that can be converted in-vivo to provide the bioactiveagent (i.e. compounds of the invention) is a prodrug within the scopeand spirit of the invention. Various forms of prodrugs are well known inthe art and are described (e.g. Wermuth C G et al., Chapter 31: 671-696,The Practice of Medicinal Chemistry, Academic Press 1996; Bundgaard H,Design of Prodrugs, Elsevier 1985; Bundgaard H, Chapter 5: 131-191, ATextbook of Drug Design and Development, Harwood Academic Publishers1991). Said references are incorporated herein by reference. It isfurther known that chemical substances are converted in the body intometabolites which may where appropriate likewise elicit the desiredbiological effect—in some circumstances even in more pronounced form.Any biologically active compound that was converted in-vivo bymetabolism from any of the compounds of the invention is a metabolitewithin the scope and spirit of the invention.

The compounds of the invention may be present in the form of theirdouble bond isomers as pure E or Z isomers, or in the form of mixturesof these double bond isomers. Where possible, the compounds of theinvention may be in the form of the tautomers, such as keto-enoltautomers. All stereoisomers of the compounds of the invention arecontemplated, either in a mixture or in pure or substantially pure form.The compounds of the invention can have asymmetric centers at any of thecarbon atoms. Consequently, they can exist in the form of theirracemates, in the form of the pure enantiomers and/or diastereomers orin the form of mixtures of these enantiomers and/or diastereomers. Themixtures may have any desired mixing ratio of the stereoisomers. Thus,for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor nonchiral phases or by recrystallization from an optionally opticallyactive solvent or with use of an optically active acid or base or byderivatization with an optically active reagent such as, for example, anoptically active alcohol, and subsequent elimination of the radical.

The invention also relates to the use of mixtures of the compoundsaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organization for chemical compounds and especially organiccompounds. The terms indicated for explanation of the above compounds ofthe invention always, unless indicated otherwise in the description orin the claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents. The term “substituted” means that thecorresponding radical, group or moiety has one or more substituents.Where a radical has a plurality of substituents, and a selection ofvarious substituents is specified, the substituents are selectedindependently of one another and do not need to be identical. Eventhough a radical has a plurality of a specific-designated substituent(e.g. Y₂ or YY) the expression of such substituent may differ from eachother (e.g. methyl and ethyl). It shall be understood accordingly that amultiple substitution by any radical of the invention may involveidentical or different radicals. Hence, if individual radicals occurseveral times within a compound, the radicals adopt the meaningsindicated, independently of one another. In case of a multiplesubstitution, the radical could be alternatively designated with R′, R″,R′″, R″″ etc.

The terms “alkyl” or “A” refer to acyclic saturated or unsaturatedhydrocarbon radicals, which may be branched or straight-chain andpreferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e.C₁-C₁₀-alkanyls. Examples of suitable alkyl radicals are methyl, ethyl,n-propyl, isopropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1-or 2-ethylbutyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-,3- or -methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl,n-octadecyl, n-icosanyl, n-docosanyl.

In a preferred embodiment of the invention, A denotes unbranched orbranched alkyl having 1-10 C atoms, in which 1-7H atoms may be replacedindependently from one another by Hal and/or OH. A more preferred Adenotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4atoms may be replaced independently from one another by Hal and/or OH.In a most preferred embodiment of the invention, A denotes unbranched orbranched alkyl having 1-5 C atoms, in which 1-3H atoms can be replacedindependently from one another by Hal or OH. It is highly preferred thatA denotes unbranched or branched alkyl having 1-5 C atoms, in which 1-3Hatoms can be replaced independently from one another by F and/or CI.Particularly preferred is C₁₋₄-alkyl. A C₁₋₄-alkyl radical is forexample a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especiallymethyl, ethyl, propyl or trifluoromethyl. It shall be understood thatthe respective denotation of A is independently of one another in anyradical of the invention.

The terms “cycloalkyl” or “Cyc” for the purposes of this inventionrefers to saturated and partially unsaturated non-aromatic cyclichydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20,preferably 3 to 12, more preferably 3 to 9 carbon atoms. The cycloalkylradical may also be part of a bi- or polycyclic system, where, forexample, the cycloalkyl radical is fused to an aryl, heteroaryl orheterocyclyl radical as defined herein by any possible and desired ringmember(s). The bonding to the compounds of the general formula (I) canbe effected via any possible ring member of the cycloalkyl radical.Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,cyclohexenyl, cyclopentenyl and cyclooctadienyl.

In a preferred embodiment of the invention, Cyc denotes cycloalkylhaving 3-6 C atoms, in which 1-4H atoms may be replaced by OH. Morepreferred is C₃-C₆-cycloalkyl, i.e. cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl. Moreover, the definition of A shall also comprisecycloalkyls and it is to be applied mutatis mutandis to Cyc. It shall beunderstood that the respective denotation of Cyc is independently of oneanother in any radical of the invention.

The term “aryl” or “carboaryl” for the purposes of this invention refersto a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14,preferably 5 to 10, more preferably 6 to 8 carbon atoms, which can beoptionally substituted. The term “aryl” also includes systems in whichthe aromatic cycle is part of a bi- or polycyclic saturated, partiallyunsaturated and/or aromatic system, such as where the aromatic cycle isfused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group asdefined herein via any desired and possible ring member of the arylradical. The bonding to the compounds of the general formula (I) can beeffected via any possible ring member of the aryl radical. Examples ofsuitable aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl,2-naphthyl and anthracenyl, but likewise in-danyl, indenyl or1,2,3,4-tetrahydronaphthyl. Preferred carboaryls of the invention areoptionally substituted phenyl, naphthyl and biphenyl, more preferablyoptionally substituted monocylic carboaryl having 6-8 C atoms, mostpreferably optionally substituted phenyl.

In another embodiment of the invention, a carbocycle, including, but notlimited to, carboaryl, is defined as “Ar”. Examples of suitable Arradicals are phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-,m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-sulfonamido-phenyl, o-, m- or p-(N-methyl-sulfonamido)phenyl, o-, m-or p-(N,N-dimethyl-sulfonamido)phenyl, o-, m- orp-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes an unsaturated or aromatic mono- or bicycliccarbocycle having 3-10 C atoms, which can be substituted by at least onesubstituent selected from the group of A, Hal, OY, COOY, CONH₂, NHCOY,NY₂, NO₂, SO₂Y, CN and Het², or which can be fused to Cyc. In a morepreferred embodiment of the invention, Ar denotes an unsaturated oraromatic mono- or bicyclic carbocycle having 5-10 C atoms, which can besubstituted by at least one substituent selected from the group of A,Hal, OY, COOY, CONH₂, NHCOY, NY₂, NO₂, CN and Het². It is most preferredthat Ar denotes an aromatic monocyclic carbocycle having 6-8 C atoms,which can be mono- or disubstituted by at least one substituent selectedfrom the group of A, Hal, OA, CONH₂, NY₂, NO₂ and CN. In another aspectof the invention, Ar preferably denotes an unsaturated or aromatic mono-or bicyclic carbocycle having 3-10 C atoms, which can be substituted byat least one substituent selected from the group of A, Hal,—(CY₂)_(n)—OY, COOY, CONH₂, NHCOY, —(CY₂)_(n)—NYCOOY, —(CY₂)_(n)—NY₂,NO₂, SO₂Y, SO₂NY₂, NYSO₂Y, —(CY₂)_(n)—CN, —(CY₂)_(n)-Het² and Cyc, orwhich can be fused to Cyc. In another more preferred embodiment of theinvention, Ar denotes an unsaturated or aromatic mono- or bicycliccarbocycle having 5-10 C atoms, which can be substituted by at least onesubstituent selected from the group of A, Hal, OY, COOY, CONH₂, NHCOY,—(CH₂)_(n)—NY₂, SO₂NH₂, NO₂, CN and Het². It is another most preferredaspect that Ar denotes an aromatic monocyclic carbocycle having 6-8 Catoms, which can be mono- or disubstituted by at least one substituentselected from the group of A, Hal, OY, CONH₂, —(CH₂)_(n)-NA₂, SO₂NH₂ andHet². In a highly preferred embodiment of the invention, Ar denotesphenyl, which can be monosubstituted by A, Hal or OA. Particularlypreferred Ar is phenyl, which is monosubstituted by A. It shall beunderstood that the respective denotation of Ar is independently of oneanother in any radical of the invention.

The term “heteroaryl” for the purposes of this invention refers to a1-15, preferably 1-9, most preferably 5-, 6- or 7-membered mono- orpolycyclic aromatic hydrocarbon radical which comprises at least 1,where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen,oxygen and/or sulfur, where the heteroatoms are identical or different.Preferably, the number of nitrogen atoms is 0, 1, 2, 3 or 4, and that ofthe oxygen and sulfur atoms is independently from one another 0 or 1.The term “heteroaryl” also includes systems in which the aromatic cycleis part of a bi- or polycyclic saturated, partially unsaturated and/oraromatic system, such as where the aromatic cycle is fused to an aryl,cycloalkyl, heteroaryl or heterocyclyl group as defined herein via anydesired and possible ring member of the heteroaryl radical. The bondingto the compounds of the general formula (I) can be effected via anypossible ring member of the heteroaryl radical. Examples of suitableheteroaryl are pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl,imidazolyl, triazolyl, triazinyl, tetrazolyl, phthalazinyl, indazolyl,indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl,phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.

It is preferred that heteroaryl in the realms of “Het¹” represents anunsaturated or aromatic mono- or bicyclic heterocycle having 1-10 Catoms and 1-4 N, O and/or S atoms, which can be substituted by at leastone substituent selected from the group of Hal, A, Cyc, OY, ═O, COOY,CONH₂, NHCOY, —(CY₂)_(n)—NY₂, SO₂Y, SO₂NY₂, NHSO₂Y, CN, Ar and—(CY₂)_(n)-Het³. In a more preferred embodiment of the invention, Het¹denotes an unsaturated or aromatic mono- or bicyclic heterocycle having1-10 C atoms and 1-4 N, O and/or S atoms, which can be substituted by atleast one substituent selected from the group of Hal, A, Cyc, OY, COOY,CONH₂, NHCOY, NY₂, SO₂Y, SO₂NY₂, NHSO₂Y, CN and Ar. In a most preferredembodiment of the invention, Het¹ denotes an unsaturated or aromaticmono- or bicyclic heterocycle having 1-9 C atoms and 1-3 N, O and/or Satoms, which can be mono- or disubstituted by at least one substituentselected from the group of Hal, A, Cyc, OY, CONH₂, NHCOY,—(CH₂)_(n)—NY₂, SO₂NY₂, NHSO₂Y, CN and Ar. In another most preferredembodiment of the invention, Het¹ denotes an unsaturated or aromaticmonocyclic heterocycle having 1-6 C atoms and 1-3 N, O and/or S atoms,which can be mono- or disubstituted by at least one substituent selectedfrom the group of Hal, A, Cyc, OA, CONH₂, NHCOA, NHA, SO₂NH₂ and CN, oran aromatic bicyclic heterocycle having 6-9 C atoms and 1-3 N and/or Satoms, which can be monosubstituted by A. It is highly preferred thatHet¹ denotes pyrrolyl, furyl, thiophenyl, imidazolyl, pyrazyl, oxazyl,isoxazyl, thiazyl, thiadiazyl, tetrazyl, pyridyl, pyrimidyl, indolyl,benzimidazolyl, benzothiazyl, quinolyl, isoquinolyl or quinoxalyl, whichcan be monosubstituted by Hal, A or Cyc. Particularly highly preferredHet¹ is pyrrolyl, furyl, thiophenyl, imidazolyl, pyrazyl, oxazyl,isoxazyl, thiazyl, thiadiazyl, tetrazyl, pyridyl or pyrimidyl, which canbe monosubstituted by Hal, Cyc or —(CH₂)_(n)-NA₂. It shall be understoodthat the respective denotation of Het¹ is independently of one anotherin any radical of the invention.

It is preferred that heteroaryl in the realms of “Het²” represents asaturated or unsaturated monocyclic 5- or 6-membered heterocycle having1-4 C atoms and 1-4 N, O and/or S atoms, which can be substituted by Aand/or ═O. In a more preferred embodiment of the invention, Het² denotesan unsaturated monocyclic 5-membered heterocycle having 1-3 C atoms and2-4 N and/or S atoms, which can be substituted by A. In a most preferredembodiment of the invention, Het² denotes imidazolyl, pyrazyl, thiazylor tetrazyl, which can be monosubstituted by methyl. It is a highlypreferred embodiment of the invention that Het² denotes tetrazyl.

The terms “heterocycle” or “heterocyclyl” for the purposes of thisinvention refers to a mono- or polycyclic system of 3 to 20 ring atoms,preferably 3 to 14 ring atoms, more preferably 3 to 10 ring atoms,comprising carbon atoms and 1, 2, 3, 4 or 5 heteroatoms, which areidentical or different, in particular nitrogen, oxygen and/or sulfur.The cyclic system may be saturated or mono- or poly-unsaturated. In thecase of a cyclic system consisting of at least two rings the rings maybe fused or spiro or otherwise connected. Such heterocyclyl radicals canbe linked via any ring member. The term “heterocyclyl” also includessystems in which the heterocycle is part of a bi- or polycyclicsaturated, partially unsaturated and/or aromatic system, such as wherethe heterocycle is fused to an aryl, cycloalkyl, heteroaryl orheterocyclyl group as defined herein via any desired and possible ringmember of the heterocyclyl radical. The bonding to the compounds of thegeneral formula (I) can be effected via any possible ring member of theheterocyclyl radical. Examples of suitable heterocyclyl radicals arepyrrolidinyl, thiapyrrolidinyl, piperidinyl, piperazinyl,oxapiperazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuryl,imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinyl,tetrahydrothiophenyl, dihydropyranyl.

In a preferred embodiment of the invention, the term “Het³” denotes asaturated mono- or bicyclic heterocycle having 3-7 C atoms and 1-4 N, Oand/or S atoms, which can be substituted by at least one substituentselected from the group of ═O, A, Hal, —(CY₂)_(n)-Cyc, —(CY₂)_(n)—OY,COY, COOY, CONY₂, NHCOY, —(CH₂)_(n)—NY₂, CN, SO₂Y and —(CY₂)_(n)—Ar. Ina more preferred embodiment of the invention, Het³ denotes a saturatedmonocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S atoms,which can be mono-, di- or trisubstituted by at least one substituentselected from the group of ═O, A, Hal, —(CY₂)_(n)-Cyc, —(CY₂)_(n)—OY,COY, COOY, CONY₂, NHCOY, NY₂, CN, SO₂Y and —(CY₂)_(n)—Ar. In a mostpreferred embodiment of the invention, Het³ denotes a saturatedmonocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S atoms,which can be mono-, di- or trisubstituted by at least one substituentselected from the group of ═O, A, Cyc, OY, COA, COOA, CONHA and SO₂A. Itis highly preferred that Het³ denotes pyrrolidinyl, oxolanyl,imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl,thiomorpholinyl, which can be monosubstituted by ═O. Particularlypreferred Het³ is pyrrolidinyl, oxolanyl, imidazolidinyl, thiazolidinyl,piperidinyl, piperazinyl, thiomorpholinyl, which is monosubstituted by═O. It shall be understood that the respective denotation of Het³ isindependently of one another in any radical of the invention.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (CI,chloro) or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine. Halogenpreferably means a fluorine, chlorine or bromine atom. Fluorine andchlorine are more preferred, when the halogens are substituted on analkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O). It shall beunderstood that the respective denotation of Hal is independently of oneanother in any radical of the invention.

It is a preferred embodiment of the present invention that both W¹ andW² denote N.

It is another preferred embodiment of the present invention that thephenyl ring in the scaffold of formula (I) is substituted by —CONR¹R² inmeta position with regard to the —NXR³R⁴ moiety.

It is a preferred embodiment of the R¹ radical according to the presentinvention to be —(CY₂)_(n)-E-Het³, —(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)-Het¹,—(CY₂)_(n)—NHCO-Het¹, —(CY₂)_(n)—Ar, —(CY₂)_(n)-Cyc,—(CY₂)_(n)—CONH-Cyc, A, —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY,—(CYR⁸)_(n)—NY₂, —(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCOOY or—(CY₂)_(n)—NHCO—CH═CH₂, more preferably —(CY₂)_(n)-E-Het³,—(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)-Het¹, —(CY₂)_(n)—NHCO-Het¹,—(CY₂)_(n)—Ar, —(CY₂)_(n)-Cyc, —(CY₂)_(n)—CONH-Cyc, A, —(CYR⁸)_(n)—OH,—(CY₂)_(n)—COOA, —(CYR⁸)_(n)—NY₂, —(CYR⁸)_(n)—NACOA, —(CY₂)_(n)—NHCOOAor —(CY₂)_(n)—NHCO—CH═CH₂, most preferably —(CY₂)_(n)-E-Het³,—(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)-Het¹, —(CY₂)_(n)—NHCO-Het¹,—(CY₂)_(n)—Ar, —(CY₂)_(n)-Cyc or —(CY₂)_(n)—CONH-Cyc, highly preferably—(CY₂)_(n)-E-Het³, —(CY₂)_(n)-Het¹ or —(CY₂)_(n)—Ar, particularlypreferably —(CY₂)_(n)-Het³.

It is another preferred embodiment of the R¹ radical according to thepresent invention to be —(CY₂)_(n)-E-(CY₂)_(n)-Het³,—(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)—NHCO-Het³,—(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³, —(CY₂)_(n)-Het¹,—(CY₂)_(n)—NHCO-Het¹, —(CY₂)_(n)—Ar, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)—Ar,—(CY₂)_(n)-Cyc, —(CY₂)_(n)—CONH-Cyc, A, —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY,—(CYR⁸)_(n)—CO—(CY₂)_(n)—N(R⁸)₂,—(CY₂)_(n)—[C(Y)OH]]_(m)—(CYR⁸)_(n)—NY₂,[—(CY₂)_(n)—O]_(m)—(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCOOY,—(CY₂)_(n)—NYCON(R⁸)₂, —(CY₂)_(n)—NHCO—CH═CH₂ or—(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂, more preferably —(CY₂)_(n)-E-Het³,—(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)—NHCO-Het³,—(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³, —(CY₂)_(n)-Het¹,—(CY₂)_(n)—NHCO-Het¹, —(CY₂)_(n)—Ar, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)—Ar,—(CY₂)_(n)-Cyc, —(CY₂)_(n)—CONH-Cyc, A, —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY,—(CY₂)_(n)—CO—NY₂, —(CYR⁸)_(n)—NY₂, —(CYR⁸)_(n)—NYCOY,—(CY₂)_(n)—NYCOOY, —(CY₂)_(n)—NYCON(R⁸)₂, —(CY₂)_(n)—NHCO—CH═CH₂ or—(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂.

It is another more preferred embodiment of the R¹ radical according tothe present invention to be —(CY₂)_(n)-E-(CY₂)_(n)-Het³,—(CY₂)_(n)—NHCO-Het³, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³,—(CY₂)_(n)-Het¹, —(CY₂)_(n)—Ar, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)—Ar,—(CY₂)_(n)-Cyc, —(CYR⁸)_(n)—CO—(CY₂)_(n)—N(R⁸)₂,[—(CY₂)_(n)—O]_(m)—(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCON(R⁸)₂ or—(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂, most preferably —(CY₂)_(n)-Het³,—(CY₂)_(n)—NHCO-Het³, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³,—(CY₂)_(n)-Het¹, —(CY₂)_(n)—Ar, —(CY₂)_(n)—C(Y)(OH)—Ar, Cyc,—(CY₂)_(n)—CO—NY₂, (CY₂)_(n)—NYCOY, —(CY₂)_(n)—NYCONY₂ or—(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂.

It is a preferred embodiment of the R² radical according to the presentinvention to be H.

It is another preferred embodiment that R¹, R² together also denote—(CY₂)_(p)—NH—(CY₂)_(p)—, —(CY₂)_(p)—NHCO—(CY₂)_(p)—,—(CY₂)_(p)—CONH—(CY₂)_(p)—, —(CY₂)_(p)—N(COA)-(CY₂)_(p)—,—(CY₂)_(p)—N(COOA)-(CY₂)_(p)—,

It is a preferred embodiment of the R³ radical according to the presentinvention to be Het¹, Het³, Ar, H, A or Cyc, more preferably Het¹, Het³or Ar, highly preferably Het¹ or Het³, particularly highly preferablyHet¹.

It is a preferred embodiment of the R⁴ radical according to the presentinvention to be Y, more preferably H.

It is a preferred embodiment of the R⁵ radical according to the presentinvention to be E-Ar, H, A, COOA or Het¹, more preferably E-Ar, H orCOOA. It is another more preferred embodiment of the R⁵ radicalaccording to the present invention to be E-Ar or Het¹, most preferablyE-Ar, highly preferably Ar.

It is another highly preferred embodiment of the R¹, R³, R⁵ radicalsaccording to the present invention to be independently from one another—(CY₂)_(n)-Het³, —(CY₂)_(n)-Het¹, —(CY₂)_(n)—Ar or Cyc, particularlyhighly preferably —(CY₂)_(n)-Het³, Het¹ or Ar. The aforesaid disclaimeris applicable.

It is a preferred embodiment of the R⁶, R⁷ radicals according to thepresent invention to be together —(CY₂)_(p)—.

It is a preferred embodiment of the R⁸ radical according to the presentinvention to be Y, more preferably H. It shall be understood that therespective denotation of R⁸ is independently of one another in anyradical of the invention.

It is another more preferred embodiment of the R², R⁴, R⁸ radicalsaccording to the present invention to be independently of one another H,more preferably to be H.

It is a preferred embodiment of the X radical according to the presentinvention to be —(CY₂)_(m)—, CO or SO₂, more preferably CO, SO₂ or asingle bond, most preferably CO or SO₂. It is another more preferredembodiment of the X radical according to the present invention to be—(CY₂)_(m)— or CO. A highly preferred X is CO.

It is a preferred embodiment of the E radical according to the presentinvention to be —(CY₂)_(m)—, CO, —COO— or SO₂, more preferably—(CY₂)_(m)—, CO or SO₂, most preferably —(CY₂)_(m)—. It shall beunderstood that the respective denotation of E is independently of oneanother in any radical of the invention.

In an aspect of the invention, Y denotes H or A. It shall be understoodthat the respective denotation of Y is independently of one another inany radical of the invention.

It is a preferred embodiment of the m index according to the presentinvention to be 0, 1, 2 or 3, more preferably 0, 1 or 2, most preferably0 or 1.

It is a preferred embodiment of the n index according to the presentinvention to be 0, 1, 2, 3, 4 or 5, more preferably 0, 1, 2, 3 or 4,most preferably 0, 1, 2 or 3. It shall be understood that the respectivedenotation of n is independently of one another in any radical of theinvention.

It is a preferred embodiment of the p index according to the presentinvention to be 1, 2 or 3, more preferably 2 or 3, most preferably 2. Itshall be understood that the respective denotation of p is independentlyof one another in any radical of the invention.

In another preferred embodiment of the present invention, both W¹ and W²denote N, and R⁶ and R⁷ together denote —(CY₂)_(p)—, and p denotes 2.

Accordingly, the subject-matter of the invention relates to compounds offormula (I), in which at least one of the aforementioned radicals hasany meaning, particularly realize any preferred embodiment, as describedabove. Radicals, which are not explicitly specified in the context ofany embodiment of formula (I), sub-formulae thereof or other radicalsthereto, shall be construed to represent any respective denotationsaccording to formula (I) as disclosed hereunder for solving the problemof the invention. That means that the aforementioned radicals may adoptall designated meanings as each described in the prior or followingcourse of the present specification, irrespective of the context to befound, including, but not limited to, any preferred embodiments. Itshall be particularly understood that any embodiment of a certainradical can be combined with any embodiment of one or more otherradicals.

In another preferred embodiment of the present invention, benzamidederivatives of sub-formula (I-A) are provided

wherein

-   R¹ denotes —(CY₂)_(n)-E-(CY₂)_(n)-Het³, —(CY₂)_(n)-Cyc-Het³,    —(CY₂)_(n)—NHCO-Het³, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³,    —(CY₂)_(n)-Het¹, —(CY₂)_(n)—NHCO-Het¹, —(CY₂)_(n)—Ar,    —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)—Ar, —(CY₂)_(n)-Cyc,    —(CY₂)_(n)—CONH-Cyc, A, —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY,    —(CYR⁸)_(n)—CO—(CY₂)_(n)—N(R⁸)₂,    —(CY₂)_(n)—[C(Y)OH]]_(m)—(CYR⁸)_(n)—NY₂,    [—(CY₂)_(n)—O]_(m)—(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCOOY,    —(CY₂)_(n)—NYCON(R⁸)₂, —(CY₂)_(n)—NHCO—CH═CH₂ or    —(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂;-   R³ denotes Het¹, Het³, Ar, H, A or Cyc;-   R⁵ denotes E-Ar, H, A, COOA or Het¹;-   R⁸, Y denote independently from one another H or A;-   X denotes CO or —(CY₂)_(m);-   E denotes —(CY₂)_(m)—, CO, —COO— or SO₂;-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7H atoms can be replaced independently from one another by Hal    and/or OH;-   Cyc denotes cycloalkyl having 3-7 C atoms, in which 1-4H atoms can    be replaced independently from one another by Hal and/or OH;-   Ar denotes an unsaturated or aromatic mono- or bicyclic carbocycle    having 5-10 C atoms, which can be substituted by at least one    substituent selected from the group of A, Hal, OY, COOY, CONH₂,    NHCOY, —(CH₂)_(n)—NY₂, SO₂NH₂, NO₂, CN and Het²;-   Het¹ denotes an unsaturated or aromatic mono- or bicyclic    heterocycle having 1-9 C atoms and 1-3 N, O and/or S atoms, which    can be mono- or disubstituted by at least one substituent selected    from the group of Hal, A, Cyc, OY, CONH₂, NHCOY, —(CH₂)_(n)—NY₂,    SO₂NY₂, NHSO₂Y, CN and Ar;-   Het² denotes imidazolyl, pyrazyl, thiazyl or tetrazyl, which can be    monosubstituted by methyl;-   Het³ denotes a saturated monocyclic heterocycle having 3-6 C atoms    and 1-3 N, O and/or S atoms, which can be mono-, di- or    trisubstituted by at least one substituent selected from the group    of ═O, A, Hal, —(CY₂)_(n)-Cyc, —(CY₂)_(n)—OY, COY, COOY, CONY₂,    NHCOY, NY₂, CN, SO₂Y and —(CY₂)_(n)—Ar;-   Hal denotes F, Cl, Br or I; and-   m, n denote independently from one another 0, 1, 2 or 3;

and/or a physiologically acceptable salt thereof,

with the proviso that3-(3-chloro-benzoylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-4-(4-ethyl-piperazin-1-yl)-benzamideis excluded.

In another more preferred embodiment of the present invention, benzamidederivatives of sub-formula (I-B) are provided

wherein

-   R¹ denotes —(CY₂)_(n)-Het³, —(CY₂)_(n)—NHCO-Het³,    —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³, —(CY₂)_(n)-Het¹, —(CY₂)_(n)—Ar,    —(CY₂)_(n)—C(Y)(OH)—Ar, Cyc, —(CY₂)_(n)—CO—NY₂, —(CY₂)_(n)—NYCOY,    —(CY₂)_(n)—NYCONY₂ or —(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂;-   Y denotes H or A;-   A denotes unbranched or branched alkyl having 1-6 C atoms, in which    1-4H atoms can be replaced independently from one another by Hal    and/or OH;-   Cyc denotes cycloalkyl having 3-6 C atoms, in which 1-4H atoms can    be replaced by OH;-   Ar denotes an aromatic monocyclic carbocycle having 6-8 C atoms,    which can be mono- or disubstituted by at least one substituent    selected from the group of A, Hal, OY, CONH₂, —(CH₂)_(n)-NA₂, SO₂NH₂    and Het²;-   Het¹ denotes an unsaturated or aromatic monocyclic heterocycle    having 1-6 C atoms and 1-3 N, O and/or S atoms, which can be mono-    or disubstituted by at least one substituent selected from the group    of Hal, A, Cyc and —(CH₂)_(n)-NA₂;-   Het² denotes tetrazyl;-   Het³ denotes a saturated monocyclic heterocycle having 3-6 C atoms    and 1-3 N, O and/or S atoms, which can be mono-, di- or    trisubstituted by at least one substituent selected from the group    of ═O, A and OY;-   Hal denotes F, Cl or Br; and-   n denotes 0, 1, 2 or 3;

and/or a physiologically acceptable salt thereof.

In still another more preferred embodiment of the present invention,benzamide derivatives of sub-formula (I-C) are provided

wherein

-   R¹ denotes —(CY₂)_(n)-E-Het³, —(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)-Het¹,    —(CY₂)_(n)—NHCO-Het¹, —(CY₂)_(n)—Ar, —(CY₂)_(n)-Cyc,    —(CY₂)_(n)—CONH-Cyc, A, —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY,    —(CYR⁸)_(n)—NY₂, —(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCOOY or    —(CY₂)_(n)—NHCO—CH═CH₂;-   R³ denotes Het¹, Het³, Ar, H, A or Cyc;-   R⁵ denotes E-Ar, H, A, COOA or Het¹;-   R⁸, Y denote independently from one another H or A;-   E denotes —(CY₂)_(m)—, CO, —COO— or SO₂;-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7H atoms can be replaced independently from one another by Hal    and/or OH;-   Cyc denotes cycloalkyl having 3-7 C atoms, in which 1-4H atoms can    be replaced independently from one another by Hal;-   Ar denotes an unsaturated or aromatic mono- or bicyclic carbocycle    having 5-10 C atoms, which can be substituted by at least one    substituent selected from the group of A, Hal, OY, COOY, CONH₂,    NHCOY, NY₂, NO₂, CN and Het²;-   Het¹ denotes an unsaturated or aromatic mono- or bicyclic    heterocycle having 1-9 C atoms and 1-3 N, O and/or S atoms, which    can be mono- or disubstituted by at least one substituent selected    from the group of Hal, A, Cyc, OY, CONH₂, NHCOY, NY₂, SO₂NY₂,    NHSO₂Y, CN and Ar;-   Het² denotes imidazolyl, pyrazyl, thiazyl or tetrazyl, which can be    monosubstituted by methyl;-   Het³ denotes a saturated monocyclic heterocycle having 3-6 C atoms    and 1-3 N, O and/or S atoms, which can be mono-, di- or    trisubstituted by at least one substituent selected from the group    of ═O, A, Hal, —(CY₂)_(n)-Cyc, —(CY₂)_(n)—OY, COY, COOY, CONY₂,    NHCOY, NY₂, CN, SO₂Y and —(CY₂)_(n)—Ar;-   Hal denotes F, Cl, Br or I; and-   m, n denote independently from one another 0, 1, 2 or 3;

and/or physiologically acceptable salts thereof,

with the proviso that3-(3-chloro-benzoylamino)-N-[2-(2,4-dichloro-phenyl)-ethyl]-4-(4-ethyl-piperazin-1-yl)-benzamideis excluded.

In another most preferred embodiment of the present invention, benzamidederivatives of sub-formula (I-D) are provided

wherein

-   Y denotes H or A;-   A denotes unbranched or branched alkyl having 1-6 C atoms, in which    1-4H atoms can be replaced independently from one another by Hal    and/or OH;-   Cyc denotes cycloalkyl having 3-6 C atoms;-   Ar denotes an aromatic monocyclic carbocycle having 6-8 C atoms,    which can be mono- or disubstituted by at least one substituent    selected from the group of A, Hal, OA, CONH₂, NY₂, NO₂ and CN;-   Het¹ denotes an unsaturated or aromatic monocyclic heterocycle    having 1-6 C atoms and 1-3 N, O and/or S atoms, which can be mono-    or disubstituted by at least one substituent selected from the group    of Hal, A, Cyc, OA, CONH₂, NHCOA, NHA, SO₂NH₂ and CN, or an aromatic    bicyclic heterocycle having 6-9 C atoms and 1-3 N and/or S atoms,    which can be monosubstituted by A;-   Het³ denotes a saturated monocyclic heterocycle having 3-6 C atoms    and 1-3 N, O and/or S atoms, which can be mono- or disubstituted by    at least one substituent selected from the group of ═O, A, Cyc, OY,    COA, COOA, CONHA and SO₂A;-   Hal denotes F, Cl or Br; and-   n denotes 0, 1, 2 or 3;

and/or physiologically acceptable salts thereof.

The prior teaching of the present specification concerning the compoundsof formula (I), including any radical definition and preferredembodiment thereof, is valid and applicable without restrictions to thecompounds according to sub-formulae (I-A), (I-B) and their salts ifexpedient.

Most preferred embodiments are those compounds of formulae (I), (I-A),(I-B) and (I-C) as listed in Table 1 and 2.

TABLE 1 Compounds of formulae (I), (I-A), (I-B), (I-C). Assay A: Example10; Assay B: Example 11. Assay A Assay B 0 > 10 μM 0 > 10 μM + > 1-10μM + > 1-10 μM ++ 0.1-1 μM ++ 0.1-1 μM +++ < 0.1 μM +++ < 0.1 μMStructure % at 5 μM % at 5 μM  1

++  2

+++ +  3

++  10%  4

+  5

++ +  6

++ ++  7

+  8

++  9

+++  10

39%  11

++  12

 7%  13

14%  14

++  15

++ ++  16

 17

++  18

 19

+  20

++  21

22%  22

+  23

 4%  24

+  25

+  26

+  27

++ +  28

+  29

++  30

+  31

++ ++  32

 33

+  34

+  35

++ +  36

++ ++  37

37%  38

 39

15%  40

40%  41

+  42

++  43

44%  44

44%  45

++ ++  46

10%  47

 48

+  49

++  50

 51

39%  52

 53

 54

 55

+  56

+  57

+  58

++  27%  59

+  60

 61

 62

42%  63

 64

72%  65

+  66

 67

++  68

+  69

++  70

0  71

+  72

0  73

++ +  74

++ ++  75

++ 0  76

+  77

+  78

++  79

++ ++  80

22%  81

11%  82

+  83

 8%  84

++ ++  85

++ +  86

47%  87

+  88

34%  89

++  90

++  91

+  92

+  93

++  94

48%  95

++  96

0  97

 98

+  99

35% 100

12% 101

+ 102

+ 103

+ 104

105

+++ ++ 106

33% 107

15% 108

109

10% 110

+ 111

+ 112

21% 113

114

40% 115

39% 116

++ 117

+ 118

++ 119

++ 120

++ 121

122

24% 123

124

82% 125

126

33% 127

33% 128

++ ++ 129

++ 130

+ 131

++ 132

+ 133

++ 134

+ 135

++ ++ 136

137

138

41% 139

140

++ 141

++ 142

+ 143

++ ++ 144

145

16% 146

0 147

++ ++ 148

++ 149

24% 150

++ ++ 151

++ 152

++ +++ 153

++ 154

+ 155

++ + 156

++ 157

++ 158

+++ ++ 159

160

+ 161

++ 162

++ 163

 8% 164

+ 165

0 166

20% 167

+ 168

169

+ 170

32% 171

+ 172

+ 173

+ 174

+ 175

+ 176

++ + 177

+ 178

+ 179

++ 180

181

+ 182

183

184

185

+ 186

+ 187

188

++ ++ 189

+++ ++ 190

++ 191

++ 192

++ 193

+ 194

+ 195

+ 196

22% 197

+ 198

++ 199

200

+ 201

0 202

+ 203

++ ++ 204

205

++ 206

207

++ ++ 208

+ 209

210

+ 211

212

++ 213

0 214

+ 215

216

0 217

218

++ 219

+ 220

+ 221

++ 222

++ 223

++ 224

10% + 225

++ 226

227

228

229

41% 230

231

++ 232

++ 233

++ 234

+ 235

+ 236

++ 237

++ 238

++ 239

43% 240

++ 241

++ 177% 242

+ 243

+ 244

245

12% 246

+ + 247

+++ 248

+++ 249

+ 250

+ 251

252

14% 253

24% 254

20% 255

22% 256

26% 257

21% 258

+ 259

++ 260

261

+ 262

++ 263

264

265

TABLE 2 Further compounds of formulae (I), (I-A), (I-B), (I-C). Assay A:Example 10; Assay B: Example 11. Assay A Assay B 0 > 10 μM 0 > 10 μM + >1-10 μM + > 1-10 μM ++ 0.1-1 μM ++ 0.1-1 μM +++ < 0.1 μM +++ < 0.1 μMStructure % at 5 μM % at 1.25 μM 266

+++ 267

+ 268

269

270

++ 271

++ 272

30% 273

+ 274

++ 275

++ 276

++ 277

++ 278

+ 279

++ 280

++ 281

++ 282

++ 283

+ 284

++ 285

++ 286

287

288

++ 289

++ 290

++ 291

++ 292

++ 293

++ 294

+ 295

++ 296

++ 297

++ 298

+ 299

+ 300

301

+ 302

+ 303

+ 304

+++ 79% 305

+++ 306

++ 307

++ + 308

++ 309

++ 310

++ 311

++ ++ 312

++ 313

++ 314

38% 315

47% 316

317

++ 318

++ 319

320

++ ++ 321

++ 322

++ + 323

++ 324

+ 325

++ 326

0 327

++ 328

329

330

++ 331

+++ 332

++ 333

++ 334

++ 335

336

337

338

339

340

341

342

343

+ 344

+ ++ 345

+ 346

++ 347

0 348

++ 349

++ + 350

++ 351

++ 352

++ 353

++ 354

++ 355

++ 356

++ 357

++ 358

++ 359

++ 360

+++ 361

+ 362

++ 363

++ 364

++ 365

++ +++ 366

++ 367

++ 368

++ 369

+ 370

+ 371

++ 372

++ 373

+ 374

++ 375

++ 376

++ 377

++ 378

379

++ 380

++ 381

382

++ 383

++ 384

++ 385

++ 386

++ 387

++ 388

+++ 389

0 390

++ 391

++ 392

+++ ++ 393

++ 394

++ 50% 395

++ 396

++ 397

++ 398

++ 399

++ 400

0 401

0 402

++ 403

+ 404

+ 405

++ 406

++ 407

0 408

++ 409

0 410

++ + 411

++ 412

+ 413

+ 414

++ 415

0 416

++ 417

+ 418

++ 419

0 420

0 421

0 422

0 423

0 424

++ 425

++ 426

++ 427

++ 428

0 429

++ 430

++ 431

0 432

+ 433

++ 434

++ 435

++ ++ 436

++ 437

++ 438

++ 439

+++ 440

++ 441

+++ 442

++ 443

++ 444

++ 445

+++ 446

++ 447

++ 448

++ 449

++ 450

451

++ 452

+ 453

++ 454

++ 455

++ 456

++ 457

+ 458

459

460

++ 461

++ 462

+ 463

++ 464

+ 465

++ 466

+ 467

+++ 468

+++ 469

++ 470

++ 471

++ 472

++ 473

++ 474

+++ 475

0 476

477

+++ 478

+++ 479

++ 480

+++ 481

++ 482

+ 483

+ 484

++ 485

++ 486

+ 487

+ 488

489

+ 490

+++ 491

++ 492

++ 493

++ 494

++ 495

++ 496

++ 497

+ 498

499

++ 500

++ 501

++ 502

++ 503

++ 504

++ 505

+ 506

507

++ 508

509

510

+++ + 511

++ 512

+++ 513

+ 514

48% 515

+++ 516

++ 517

++ 518

++ 519

++ 520

521

++ 522

+ 523

++ ++ 524

++ 525

++ 526

++ 0 527

++ 528

+ 529

++ + 530

+ 531

532

0 533

+ 534

535

++ 536

++ 537

++ 538

++ 539

+ 540

+ 541

542

++ 543

+ 544

+ 545

+ 546

+ 547

+ 548

+ 549

++ 550

+++ 551

+++ 552

+++ 553

++ 554

40% 555

+ 556

557

558

559

560

561

+ 562

++ 563

0 564

++ 565

++ 566

++ 567

++ 568

++ 569

+ 570

++ 571

++ 572

+++ 573

+ 574

++ 575

+++ 576

+++ 577

578

+++ 579

++ 580

++ 581

++ 582

++ 583

+ 584

+ 585

+++ 586

587

+ 588

++ 589

++ 590

++ 591

0 592

+ 593

+ 594

+ 595

+ 596

+ 597

0 598

+ 599

0 600

601

++ + 602

++ 603

604

605

+ 606

++ 607

++ 608

++ 609

++

Highly preferred embodiments are the compounds selected from the groupof

and/or physiologically acceptable salts thereof.

The benzamide derivatives according to formula (I) and the startingmaterials for its preparation, respectively, are produced by methodsknown per se, as described in the literature (for example in standardworks, such as Houben-Weyl, Methoden der organischen Chemie [Methods ofOrganic Chemistry], Georg-Thieme-Verlag, Stuttgart), i.e. under reactionconditions that are known and suitable for said reactions.

Use can also be made of variants that are known per se, but are notmentioned in greater detail herein. If desired, the starting materialscan also be formed in-situ by leaving them in the un-isolated status inthe crude reaction mixture, but immediately converting them further intothe compound according to the invention. On the other hand, it ispossible to carry out the reaction stepwise.

The reactions are preferably performed under basic conditions. Suitablebases are metal oxides, e.g. aluminum oxide, alkaline metal hydroxide(potassium hydroxide, sodium hydroxide and lithium hydroxide, interalia), alkaline earth metal hydroxide (barium hydroxide and calciumhydroxide, inter alia), alkaline metal alcoholates (potassium ethanolateand sodium propanolate, inter alia) and several organic bases(piperidine or diethanolamine, inter alia).

The reaction is generally carried out in an inert solvent. Suitableinert solvents are, for example, hydrocarbons, such as hexane, petroleumether, benzene, toluene or xylene; chlorinated hydrocarbons, such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid, aceticacid or trifluoroacetic acid (TFA); nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to TFA, H₂O, THF,tert. butanol, tert. amylalcohol, triethylamine or dioxane.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° C.and 140° C., normally between −10° C. and 130° C., preferably between30° C. and 125° C.

The present invention also relates to a process for manufacturingcompounds of formula (I) comprising the steps of:

(a) reacting a compound of formula (II)

-   -   wherein W¹, W², R³ to R⁷, R⁶, X and Y have the meaning as        defined above,    -   in the presence of a crosslinking agent and a solvent with a        compound of formula (III)

-   -   wherein R¹ and R² have the meaning as defined above,    -   to yield a compound of formula (I)

-   -   wherein W¹, W², R¹ to R⁷, R⁶, X and Y have the meaning as        defined above,

and optionally

(b) converting a base or an acid of the compound of formula (I) into asalt thereof.

The benzamide derivatives of formula (I) are accessible via the routeabove. The starting materials, including the compounds of formulae (II)and (III), are usually known to the skilled artisan, or they can beeasily prepared by known methods. Accordingly, any compound of formulae(II) and (III) can be purified, provided as intermediate product andused as starting material for the preparation of compounds of formula(I). The process step (a) is preferably performed in the presence of acrosslinking agent which is a carbodiimide derivative, particularly1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC),and/or in the presence of a solvent, which is an organic acid,particularly TFA. It is more preferred in process step (a) to apply bothEDC and TFA. In addition to tert. butyl carbamates (BOC), the skilledartisan knows other protection groups to be used in the compound offormula (III).

The compounds of formula (I) can be modified, like hydrogenated ormetal-reduced, to remove the chlorine, or put into a substitutionreaction, and/or to be transformed with an acid or base into a salt,preferably with a strong acid. Numerous papers and methods are availableand useful for the one skilled in the art in respect for organicchemistry, chemical strategies and tactics, synthetic routes, protectionof intermediates, cleavage and purification procedure, isolation andcharacterization. General chemical modifications are known to the oneskilled in the art. Halogenation of aryls or hydroxy substitution byhalogens of acids, alcohols, phenols, and their tautomeric structurescan be preferably carried out by use of POCl₃, or SOCl₂, PCl₅, SO₂Cl₂.In some instances oxalyl chloride is also useful. Temperatures can varyfrom 0° C. to reflux depending on the task to halogenate a pyridonestructure or a carboxylic acid or a sulfonic acid. Time will also beadjusted from minutes to several hours or even over night. Similarly,alkylation, ether formation, ester formation, amide formation are knownto the one skilled in the art. Arylation with aryl boronic acids can beperformed in presence of a Pd catalyst, appropriate ligand and base,preferably a carbonate, phosphate, borate salt of sodium, potassium orcesium. Organic bases, like Et₃N, DIPEA or the more basic DBU can alsobe used. Solvents can vary too, from toluene, dioxane, THF, diglyme,monoglyme, alcohols, DMF, DMA, NMP, acetonitrile, in some cases evenwater, and others. Commonly used catalysts like Pd (PPh₃)₄, or Pd(OAc)₂,PdCl₂ type precursors of PdO catalysts have advanced to more complexones with more efficient ligands. In C—C arylations instead of boronicacids and esters (Stille coupling), aryl-trifluoroborate potassium salts(Suzuki-Miyaura coupling), organo silanes (Hiyama coupling), Grignardreagents (Kumada), zink organyles (Negishi coupling) and tin organyles(Stille coupling) are useful. This experience can be transferred to N-and O-arylations. Numerous papers and methods are available and usefulfor the one skilled in the art in respect of N-arylation and even ofelectron deficient anilines (Biscoe et al. JACS 130: 6686 (2008)), andwith aryl chlorides and anilines (Fors et al. JACS 130: 13552 (2008) aswell as for O-arylation by using Cu catalysis and Pd catalysis.

In the final step of the processes above, a salt of the compoundsaccording to formulae (I) to (III), preferably formula (I), isoptionally provided. The said compounds according to the invention canbe used in their final non-salt form. On the other hand, the presentinvention also encompasses the use of these compounds in the form oftheir pharmaceutically acceptable salts, which can be derived fromvarious organic and inorganic acids and bases by procedures known in theart. Pharmaceutically acceptable salt forms of the compounds accordingto the invention are for the most part prepared by conventional methods.If the compound according to the invention contains a carboxyl group,one of its suitable salts can be formed by the reaction of the compoundwith a suitable base to give the corresponding base-addition salt. Suchbases are, for example, alkali metal hydroxides, including potassiumhydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metalhydroxides, such as barium hydroxide and calcium hydroxide; alkali metalalkoxides, for example potassium ethoxide and sodium propoxide; andvarious organic bases, such as piperidine, diethanolamine andN-methylglutamine. The aluminum salts of the compounds according to theinvention are likewise included. In the case of certain compoundsaccording to the invention, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds according to the invention include the following:acetate, adipate, alginate, arginate, aspartate, benzoate,benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate,camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate,citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Object of the present invention is also the use of compounds accordingto formula (I) and/or physiologically acceptable salts thereof formodulating an FSH receptor, particularly in the presence of FSH. Theterm “modulation” denotes any change in FSHR-mediated signaltransduction, which is based on the action of the specific inventivecompounds capable to interact with the FSHR target in such a manner thatmakes recognition, binding and activating possible. The compounds arecharacterized by such a high affinity to FSHR, which ensures a reliablebinding and preferably a positive allosteric modulation of FSHR. Morepreferably, the substances are mono-specific in order to guarantee anexclusive and directed recognition with the single FSHR target. In thecontext of the present invention, the term “recognition”—without beinglimited thereto—relates to any type of interaction between the specificcompounds and the target, particularly covalent or non-covalent bindingor association, such as a covalent bond, hydrophobic/hydrophilicinteractions, van der Waals forces, ion pairs, hydrogen bonds,ligand-receptor interactions, and the like. Such association may alsoencompass the presence of other molecules such as peptides, proteins ornucleotide sequences. The present receptor/ligand-interaction ischaracterized by high affinity, high selectivity and minimal or evenlacking cross-reactivity to other target molecules to exclude unhealthyand harmful impacts to the treated subject.

A preferred object of the present invention relates to a method formodulating an FSH receptor, preferably in a positive allosteric manner,wherein a system capable of expressing the FSH receptor, preferablyexpressing the FSH receptor, is contacted, preferably in the presence ofFSH, with at least one compound of formula (I) according to theinvention and/or physiologically acceptable salts thereof, underconditions such that said FSH receptor is modulated, preferably in apositive allosteric manner. Although a cellular system is preferred inthe scope of the invention, an in-vitro translation system can bealternatively used which is based on the protein synthesis withoutliving cells. The cellular system is defined to be any subject providedthat the subject comprises cells. Hence, the cellular system can beselected from the group of single cells, cell cultures, tissues, organsand animals. The prior teaching of the present specification concerningthe compounds of formula (I), including any preferred embodimentthereof, is valid and applicable without restrictions to the compoundsaccording to formula (I) and their salts when used in the method formodulating FSHR.

The compounds according to the invention preferably exhibit anadvantageous biological activity, which is easily demonstrated in cellculture-based assays, for example assays as described herein or in priorart (cf. e.g. WO 2002/09706, which is incorporated herein by reference).In such assays, the compounds according to the invention preferablyexhibit and cause an agonistic effect. It is preferred that thecompounds of the invention have an FSHR agonist activity, as expressedby an EC₅₀ standard, of less than 10 μM, more preferably less than 1 μM,most preferably less than 0.5 μM, highly preferably less than 0.1 μM.“EC₅₀” is the effective concentration of a compound at which 50% of themaximal response of that obtained with FSH would be obtained.

As discussed herein, these signaling pathways are relevant for variousdiseases, preferably fertility disorders. Accordingly, the compoundsaccording to the invention are useful in the prophylaxis and/ortreatment of diseases that are dependent on the said signaling pathwaysby interaction with one or more of the said signaling pathways. Thepresent invention therefore relates to compounds according to theinvention as modulators, preferably agonists, more preferably positiveallosteric modulators, of the signaling pathways described herein,preferably of the FSHR-mediated signaling pathway. The compounds of theinvention are supposed to bind to the intracellular receptor domainwithout a competitive interaction with FSH, but they act as anallosteric enhancer of FSH on its receptor. The non-competitiveinteraction refers to the nature of the agonist activity exhibited bythe compounds of the invention, wherein the compounds activate FSHRwithout substantially reducing the magnitude of binding of FSH to FSHR.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate FSHR activity, usuallybetween about one hour and one week. In-vitro treatment can be carriedout using cultivated cells from a biopsy sample or cell line. In apreferred aspect of the invention, a follicle cell is stimulated formaturation. The viable cells remaining after the treatment are countedand further processed.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing FSHR-dependent signal transduction pathways in animalsand/or cell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The modulation can bemonitored by the techniques described in the course of the presentspecification. The in-vitro use is preferably applied to samples ofhumans suffering from fertility disorders. Testing of several specificcompounds and/or derivatives thereof makes the selection of that activeingredient possible that is best suited for the treatment of the humansubject. The in-vivo dose rate of the chosen derivative isadvantageously pre-adjusted to the FSHR susceptibility and/or severityof disease of the respective subject with regard to the in-vitro data.Therefore, the therapeutic efficacy is remarkably enhanced. Moreover,the subsequent teaching of the present specification concerning the useof the compounds according to formula (I) and its derivatives for theproduction of a medicament for the prophylactic or therapeutic treatmentand/or monitoring is considered as valid and applicable withoutrestrictions to the use of the compound for the modulation of FSHRactivity if expedient.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. Preferably, the invention relates to amedicament comprising at least one compound according to the inventionand/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with FSHR activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

Consequently, the invention also relates to a pharmaceutical compositioncomprising as active ingredient at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof together with pharmaceutically tolerable adjuvants and/orexcipients. It shall be understood that the compound of the invention isprovided in an effective amount.

In the meaning of the invention, an “adjuvant” denotes every substancethat enables, intensifies or modifies a specific response against theactive ingredient of the invention if administered simultaneously,contemporarily or sequentially. Known adjuvants for injection solutionsare, for example, aluminum compositions, such as aluminum hydroxide oraluminum phosphate, saponins, such as QS21, muramyldipeptide ormuramyltripeptide, proteins, such as gamma-interferon or TNF, M59,squalen or polyols.

Furthermore, the active ingredient may be administered alone or incombination with other treatments. A synergistic effect may be achievedby using more than one compound in the pharmaceutical composition, i.e.the compound of formula (I) is combined with at least another agent asactive ingredient, which is either another compound of formula (I) or acompound of different structural scaffold. The active ingredients can beused either simultaneously or sequentially. The present compounds aresuitable for combination with known fertility-inducing agents.Preferably, the other active pharmaceutical ingredient is selected fromthe group of FSH, o-FSH (Gonal F), β-FSH, LH, hMG and2-(4-(2-chloro-1,2-diphenylethenyl)-phenoxy)-N,N-diethyl-ethanaminecitrate (Chlomifene citrate). Further ovulation adjuncts are known tothose of skill in the art (cf. e.g. WO 2002/09706, which is incorporatedherein by reference) and are useful with the compounds of the presentinvention.

The invention also relates to a set (kit) consisting of separate packsof an effective amount of a compound according to the invention and/orpharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient. The setcomprises suitable containers, such as boxes, individual bottles, bagsor ampoules. The set may, for example, comprise separate ampoules, eachcontaining an effective amount of a compound according to the inventionand/or pharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilized form.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

The pharmaceutical composition of the invention is produced in a knownway using common solid or liquid carriers, diluents and/or additives andusual adjuvants for pharmaceutical engineering and with an appropriatedosage. The amount of excipient material that is combined with theactive ingredient to produce a single dosage form varies depending uponthe host treated and the particular mode of administration. Suitableexcipients include organic or inorganic substances that are suitable forthe different routes of administration, such as enteral (e.g. oral),parenteral or topical application, and which do not react with compoundsof formula (I) or salts thereof. Examples of suitable excipients arewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, e.g. lactose orstarch, magnesium stearate, talc and petroleum jelly.

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multi-dose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilized) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavors.

In a preferred embodiment of the present invention, the pharmaceuticalcomposition is adapted for oral administration. The preparations can besterilized and/or can comprise auxiliaries, such as carrier proteins(e.g. serum albumin), lubricants, preservatives, stabilizers, fillers,chelating agents, antioxidants, solvents, bonding agents, suspendingagents, wetting agents, emulsifiers, salts (for influencing the osmoticpressure), buffer substances, colorants, flavorings and one or morefurther active substances, for example one or more vitamins. Additivesare well known in the art, and they are used in a variety offormulations.

Accordingly, the invention also relates to a pharmaceutical compositioncomprising as active ingredient at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof together with pharmaceutically tolerable adjuvants for oraladministration, optionally in combination with at least another activepharmaceutical ingredient. Both active pharmaceutical ingredients areparticularly provided in effective amount. The prior teaching of thepresent specification concerning administration route and combinationproduct, respectively, is valid and applicable without restrictions tothe combination of both features if expedient.

The terms “effective amount” or “effective dose” or “dose” areinterchangeably used herein and denote an amount of the pharmaceuticalcompound having a prophylactically or therapeutically relevant effect ona disease or pathological conditions, i.e. which causes in a tissue,system, animal or human a biological or medical response which is soughtor desired, for example, by a researcher or physician. A “prophylacticeffect” reduces the likelihood of developing a disease or even preventsthe onset of a disease. A “therapeutically relevant effect” relieves tosome extent one or more symptoms of a disease or returns to normalityeither partially or completely one or more physiological or biochemicalparameters associated with or causative of the disease or pathologicalconditions. In addition, the expression “therapeutically effectiveamount” denotes an amount which, compared with a corresponding subjectwho has not received this amount, has the following consequence:improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder. Theexpression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The respective dose or dosage range for administering the pharmaceuticalcomposition according to the invention is sufficiently high in order toachieve the desired prophylactic or therapeutic effect of reducingsymptoms of the aforementioned diseases, cancer and/or fibroticdiseases. It will be understood that the specific dose level, frequencyand period of administration to any particular human will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general state of health, gender, diet,time and route of administration, rate of excretion, drug combinationand the severity of the particular disease to which the specific therapyis applied. Using well-known means and methods, the exact dose can bedetermined by one of skill in the art as a matter of routineexperimentation. The prior teaching of the present specification isvalid and applicable without restrictions to the pharmaceuticalcomposition comprising the compounds of formula (I) if expedient.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. The concentration of the prophylactically ortherapeutically active ingredient in the formulation may vary from about0.1 to 100 wt %. Preferably, the compound of formula (I) or thepharmaceutically acceptable salts thereof are administered in doses ofapproximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, mostpreferably 5 and 100 mg per dose unit. Generally, such a dose range isappropriate for total daily incorporation. In other terms, the dailydose is preferably between approximately 0.02 and 100 mg/kg of bodyweight. The specific dose for each patient depends, however, on a widevariety of factors as already described in the present specification(e.g. depending on the condition treated, the method of administrationand the age, weight and condition of the patient). Preferred dosage unitformulations are those which comprise a daily dose or part-dose, asindicated above, or a corresponding fraction thereof of an activeingredient. Furthermore, pharmaceutical formulations of this type can beprepared using a process which is generally known in the pharmaceuticalart.

Although a therapeutically effective amount of a compound according tothe invention has to be ultimately determined by the treating doctor orvet by considering a number of factors (e.g. the age and weight of theanimal, the precise condition that requires treatment, severity ofcondition, the nature of the formulation and the method ofadministration), an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The pharmaceutical composition of the invention can be employed asmedicament in human and veterinary medicine. According to the invention,the compounds of formula (I) and/or physiologically salts thereof aresuited for the prophylactic or therapeutic treatment and/or monitoringof diseases that are caused, mediated and/or propagated by FSHRactivity. It is particularly preferred that the diseases are fertilitydisorders. It shall be understood that the host of the compound isincluded in the present scope of protection according to the presentinvention.

Particular preference is given to the stimulation of folliculardevelopment, ovulation induction, controlled ovarial hyperstimulation,assisted reproductive technology, including in-vitro fertilization, malehypogonadism and male infertility, including some types of failure ofspermatogenesis.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by FSHR activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byFSHR activity. Compounds of formula (I) and/or a physiologicallyacceptable salt thereof can furthermore be employed as intermediate forthe preparation of further medicament active ingredients. The medicamentis preferably prepared in a non-chemical manner, e.g. by combining theactive ingredient with at least one solid, fluid and/or semi-fluidcarrier or excipient, and optionally in conjunction with a single ormore other active substances in an appropriate dosage form.

Another object of the present invention are compounds of formula (I)according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byFSHR activity. Another preferred object of the invention concernscompounds of formula (I) according to the invention and/orphysiologically acceptable salts thereof for use in the prophylactic ortherapeutic treatment and/or monitoring of fertility disorders. Theprior teaching of the present specification concerning the compounds offormula (I), including any preferred embodiment thereof, is valid andapplicable without restrictions to the compounds according to formula(I) and their salts for use in the prophylactic or therapeutic treatmentand/or monitoring of fertility disorders.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition.

Monitoring is considered as a kind of treatment provided that thecompounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The medicament can also be used to reducing thelikelihood of developing a disorder or even prevent the initiation ofdisorders associated with FSHR activity in advance or to treat thearising and continuing symptoms. The disorders as concerned by theinvention are preferably fertility disorders.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

It is another object of the invention to provide a method for treatingdiseases that are caused, mediated and/or propagated by FSHR activity,wherein at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof is administered to amammal in need of such treatment. It is another preferred object of theinvention to provide a method for treating fertility disorders, whereinat least one compound of formula (I) according to the invention and/orphysiologically acceptable salts thereof is administered to a mammal inneed of such treatment. The compound is preferably provided in aneffective amount as defined above. The preferred treatment is an oraladministration. In another preferred aspect, the method of treatmentaims to achieve ovulation induction and/or controlled ovarianhyperstimulation. In still another preferred aspect, the method oftreatment forms the basis for a method for in-vitro fertilizationcomprising the steps of: (a) treating a mammal according to the methodof treatment as described above, (b) collecting ova from said mammal,(c) fertilizing said ova, and (d) implanting said fertilized ova into ahost mammal. The host mammal can be either the treated mammal (i.e. thepatient) or a surrogate. The prior teaching of the invention and itsembodiments is valid and applicable without restrictions to the methodsof treatment if expedient.

In the scope of the present invention, novel benzamide compounds offormula (I) are provided for the first time. The low molecular weightcompounds of the invention are strong and selective modulators of theFSH receptor. Their selectivity to the FSH receptor is 10-fold over theLH receptor and even 100-fold over the TSH receptor while the IC₅₀amounts to more than 10 μM on unrelated G protein-coupled receptors(GPCR) or non-GPCR targets. The current invention comprises the use ofpresent benzamide derivatives in the regulation and/or modulation of theFSHR signal cascade, which can be advantageously applied as researchtool, for diagnosis and/or in treatment of any disorder arising fromFSHR signaling.

For example, the compounds of the invention are useful in-vitro asunique tools for understanding the biological role of FSH, including theevaluation of the many factors thought to influence, and be influencedby, the production of FSH and the interaction of FSH with the FSHR (e.g.the mechanism of FSH signal transduction/receptor activation). Thepresent compounds are also useful in the development of other compoundsthat interact with FSHR since the present compounds provide importantstructure-activity relationship (SAR) information that facilitate thatdevelopment. Compounds of the present invention that bind to FSHR can beused as reagents for detecting FSHR on living cells, fixed cells, inbiological fluids, in tissue homogenates, in purified, naturalbiological materials, etc. For example, by labeling such compounds, onecan identify cells having FSHR on their surfaces. In addition, based ontheir ability to bind FSHR, compounds of the present invention can beused in in-situ staining, FACS (fluorescence-activated cell sorting),western blotting, ELISA (enzyme-linked immunoadsorptive assay), etc.,receptor purification, or in purifying cells expressing FSHR on the cellsurface or inside permeabilized cells.

The compounds of the invention can also be utilized as commercialresearch reagents for various medical research and diagnostic uses. Suchuses can include but are not limited to: use as a calibration standardfor quantifying the activities of candidate FSH agonists in a variety offunctional assays; use as blocking reagents in random compoundscreening, i.e. in looking for new families of FSH receptor ligands, thecompounds can be used to block recovery of the presently claimed FSHcompounds; use in the co-crystallization with FSHR receptor, i.e. thecompounds of the present invention will allow formation of crystals ofthe compound bound to FSHR, enabling the determination ofreceptor/compound structure by x-ray crystallography; other research anddiagnostic applications, wherein FSHR is preferably activated or suchactivation is conveniently calibrated against a known quantity of an FSHagonist, etc.; use in assays as probes for determining the expression ofFSHR on the surface of cells; and developing assays for detectingcompounds which bind to the same site as the FSHR binding ligands.

The low molecular weight inhibitors can be applied either themselvesand/or in combination with physical measurements for diagnostics oftreatment effectiveness. Medicaments and pharmaceutical compositionscontaining said compounds and the use of said compounds to treatFSHR-mediated conditions is a promising, novel approach for a broadspectrum of therapies causing a direct and immediate improvement in thestate of health, whether in man and animal. The impact is of specialbenefit to efficiently combat infertility, either alone or incombination with other fertility-inducing treatments. In particular, thecompounds of the invention potentiate the native FSH effect for bothovulation induction and assisted reproductive technology. The orallybioavailable and active new chemical entities of the invention improveconvenience for patients and compliance for physicians.

The compounds of the invention are active in the primary screen (CHOwith or without FSH), selective in secondary screen (no or low activityagainst TSHR and LHR) and potent in the granulosa cell estrodiol assay.Neither hERG nor any toxic effects could be observed in-vitro.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

All the references cited herein are incorporated by reference in thedisclosure of the invention hereby.

It is to be understood that this invention is not limited to theparticular compounds, pharmaceutical compositions, uses and methodsdescribed herein, as such matter can, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to limit thescope of the present invention, which is only defined by the appendedclaims. As used herein, including the appended claims, singular forms ofwords such as “a,” “an,” and “the” include their corresponding pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “a compound” includes a single or several differentcompounds, and reference to “a method” includes reference to equivalentsteps and methods known to a person of ordinary skill in the art, and soforth. Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by a person ofordinary skill in the art to which this invention belongs.

The techniques that are essential according to the invention aredescribed in detail in the specification. Other techniques which are notdescribed in detail correspond to known standard methods that are wellknown to a person skilled in the art, or the techniques are described inmore detail in cited references, patent applications or standardliterature. Although methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, suitable examples are described below. The followingexamples are provided by way of illustration and not by way oflimitation. Within the examples, standard reagents and buffers that arefree from contaminating activities (whenever practical) are used. Theexample are particularly to be construed such that they are not limitedto the explicitly demonstrated combinations of features, but theexemplified features may be unrestrictedly combined again if thetechnical problem of the invention is solved. Similarly, the features ofany claim can be combined with the features of one or more other claims.

In the following examples, “conventional workup” means: water was addedif necessary, the pH was adjusted, if necessary, to a value of between 2and 10, depending on the constitution of the end product, the mixturewas extracted with ethyl acetate or dichloromethane, the phases wereseparated, the organic phase was dried over sodium sulfate andevaporated, and the product was purified by chromatography on silica geland/or by crystallization. R_(t) values were determined on silica gel.The eluent was ethyl acetate/methanol 9:1.

Standard Description of Analytical Equipment

NMR Spectra were acquired on a Varian ^(Unity)Inova 400 MHz NMRspectrometer equipped with an Automation Triple Broadband (ATB) probe.The ATB probe was simultaneously tuned to ¹H, ¹⁹F and ¹³C. For typical¹H NMR spectra, the pulse angle was 45 degrees, 8 scans were summed andthe spectral width was 16 ppm (−2 ppm to 14 ppm). A total of 32768complex points were collected during the 5.1 second acquisition time,and the recycle delay was set to 1 second. Spectra were collected at 25°C. ¹H NMR Spectra are typically processed with 0.2 Hz line broadeningand zero-filling to 131072 points prior to Fourier transformation.

Method A (Rapid LC): A Shimadzu Shim-pack XR-ODS, 3.0×30 mm, 2.2 m, wasused at a temperature of 50° C. and at a flow rate of 1.5 mL/min, 2 μLinjection, mobile phase: (A) water with 0.1% formic acid and 1%acetonitrile, mobile phase (B) methanol with 0.1% formic acid; retentiontime given in minutes. Method details: (I) runs on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 massspectrometer in positive and negative ion electrospray mode withUV-detection at 220 and 254 nm with a gradient of 15-95% (B) in a 2.2min linear gradient, (II) hold for 0.8 min at 95% (B), (III) decreasefrom 95-15% (B) in a 0.1 min linear gradient, and (IV) hold for 0.29 minat 15% (B).

Method B (Polar Stop-Gap): An Agilent Zorbax Bonus RP, 2.1×50 mm, 3.5 m,was used at a temperature of 50° C. and at a flow rate of 0.8 mL/min, 2μL injection, mobile phase: (A) water with 0.1% formic acid and 1%acetonitrile, mobile phase (B) methanol with 0.1% formic acid; retentiontime given in minutes. Method details: (I) runs on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 massspectrometer in positive and negative ion electrospray mode withUV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 minlinear gradient, (II) hold for 0.5 min at 95% (B), (III) decrease from95-5% (B) in a 0.1 min linear gradient, and (IV) hold for 0.29 min at 5%(B).

Preparative HPLC was performed using a system controlled by Chromeleonsoftware and consisting of two Varian PrepStar Model 218 Pumps, a VarianProStar Model 320 UV/Vis detector, a SEDEX 55 ELSD detector, and aGilson 215 liquid handler. Typical HPLC mobile phases consist of waterand methanol. The standard column is a Varian Dynamax 21.4 mm diameterMicrosorb Guard-8 C18 column.

Rt: Retention time

Example 1 Synthetic route towards furan-2-carboxylic acid[5-((S)-1-phenyl-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 11)

Step 1

To a solution of 4-fluoro-3-nitro-benzoic acid (6.0 g, 32.4 mmol) in DMF(20 mL), K₂CO₃ (8.94 g, 64.8 mmol) was added, followed by1-o-tolyl-piperazine (6.85 g, 38.9 mmol), and the reaction mixture wasstirred at room temperature for 16 h. DMF (5.0 mL) was added andfiltered. The solid was washed with MeOH (300 mL) and methanol layer wasevaporated to give the acid 3-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid in the first crop (4.0 g, 36%).

Step 2

In a mixture of EtOH (100 mL) and MeOH (100 mL) compound acid3-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (2.0 g, 5.86 mmol) wasdissolved and evacuated for 5 min. This was added to a 3-necked flaskcontaining Pd/C (0.2 g of 5 wt %) under nitrogen. The reaction mixturewas evacuated and nitrogen purged two times and stirred under a balloonof hydrogen for 4 h. LC-MS indicated the completion of reaction and thecontents were evacuated and nitrogen purged and filtered through celite,and concentrated to give the aniline3-amino-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (1.7 g, 94%).

Step 3

In CH₂Cl₂ (50 mL) aniline 3-amino-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid (1.5 g, 4.8 mmol) was taken with TEA (3.3 mL, 24 mmol) and cooledto 0° C. Furoyl chloride (1.38 g, 10.6 mmol) in CH₂Cl₂ (5.0 mL) wasadded dropwise and the reaction was stirred at 0-25° C. for 6 h. Thereaction mixture was concentrated and dissolved in a mixture of MeOH (20mL) and THF (20 mL) and stirred with a solution of 2N NaOH (20 mL) for 2h. The solvents were removed and the contents were dissolved in waterand the solution was brought to pH 5.0 using 2 N HCl.

The solid product3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acidwas filtered and dried (1.1 g, 56%).

Step 4

To a solution of3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid(0.1 g, 0.247 mmol) and HOBt (0.05 g, 0.37 mmol) in CH₂Cl₂ (3.0 mL),a-methyl benzyl amine (0.035 g, 0.296 mmol) was added, followed byEDC.HCl (0.05 g, 0.321 mmol), and the reaction mixture was stirred atroom temperature for 3 h. The crude was diluted with CH₂Cl₂ (10.0 mL)and washed with water, concentrated and purified on silica gel columnusing CH₂Cl₂/MeOH (10%) as eluent to give off-white solid which wastreated with 5 mL of 2 M HCl in dioxane followed by ether. Theprecipitated product was filtered and dried (0.02 g, 16% yield).

LCMS (ESI) 509 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.48 (m, 3H)2.28 (brs, 3H) 3.05 (s, 9H) 5.13 (quin, J=7.42 Hz, 1H) 6.69 (dd, J=3.47,1.76 Hz, 1H) 6.93-6.99 (m, 1H) 7.06-7.11 (m, 1H) 7.14-7.21 (m, 3H)7.26-7.31 (m, 3H) 7.33-7.38 (m, 3H) 7.69 (dd, J=8.35, 2.00 Hz, 1H)7.95-8.00 (m, 1H) 8.57 (d, J=2.00 Hz, 1H) 8.74 (d, J=8.05 Hz, 1H) 9.42(s, 1H).

The preparation of following compounds was in line with Scheme 1:

Furan-2-carboxylic acid[5-[2-(1H-indol-3-yl)-ethylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 10) was prepared following the same procedure as compoundno. 11 from the intermediate acid3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 548 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 2.32 (s, 3H)3.03-3.09 (m, 2H) 3.12 (s, 8H) 3.65 (t, J=7.44 Hz, 2H) 6.67 (dd, J=3.54,1.78 Hz, 1H) 6.93-7.00 (m, 2H) 7.02-7.08 (m, 1H) 7.10 (s, 1H) 7.13-7.18(m, 3H) 7.27-7.33 (m, 2H) 7.37 (d, J=8.30 Hz, 1H) 7.54-7.62 (m, 2H) 7.80(d, J=1.03 Hz, 1H) 8.64 (d, J=2.05 Hz, 1H).

4-[3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-piperidine-1-carboxylicacid tert-butyl ester (compound no. 49) was prepared following the sameprocedure as compound no. 11 from the intermediate acid3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 588 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.36-1.42 (m, 1H) 1.42-1.46 (m, 10H) 1.59 (brs, 1H) 1.93-2.08 (m, 2H)2.34 (s, 3H) 2.90 (t, J=11.27 Hz, 2H) 3.07-3.22 (m, 8H) 3.94-4.18 (m,3H) 6.10 (d, J=7.76 Hz, 1H) 6.60 (dd, J=3.51, 1.76 Hz, 1H) 7.01 (td,J=7.33, 1.24 Hz, 1H) 7.09-7.15 (m, 1H) 7.17-7.24 (m, 3H) 7.30-7.36 (m,1H) 8.80 (d, J=2.10 Hz, 1H) 9.43 (s, 1H).

Furan-2-carboxylic acid[5-(1-acetyl-piperidin-4-ylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 56) was prepared as follows:4-[3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-piperidine-1-carboxylicacid tert-butyl ester (0.35 g, 0.59 mmol) was stirred with a mixture ofCH₂Cl₂ (5.0 mL) and TFA (3.0 mL) for 6 h. The reaction was concentratedto give the intermediate salt (0.225 g). The TFA salt offuran-2-carboxylic acid[5-(piperidin-4-ylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(0.06 g, 0.123 mmol) was dissolved in CH₂Cl₂ (5.0 mL) and DIPEA (0.2 mL,1.23 mmol) was added to this followed by acetic anhydride (0.062 g,0.615 mmol). The reaction mixture was stirred at room temperature for 1h. Reaction was concentrated and dissolved in methanol and purified onpreparative HPLC using MeOH/water as eluent to give the product (0.025g, 38%).

LCMS (ESI) 530 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33-1.52 (m,3H) 1.96-2.07 (m, 1H) 2.10 (s, 3H) 2.34 (s, 3H) 2.76 (t, J=11.42 Hz, 1H)3.12 (dd, J=19.38, 5.61 Hz, 8H) 3.19-3.25 (m, 1H) 3.82 (d, J=12.15 Hz,1H) 4.12-4.26 (m, 1H) 4.59 (d, J=14.10 Hz, 1H) 6.23 (d, J=7.71 Hz, 1H)6.58 (dd, J=3.47, 1.76 Hz, 1H) 6.99-7.06 (m, 1H) 7.07-7.14 (m, 1H) 7.21(d, J=5.32 Hz, 1H) 7.25 (s, 1H) 7.31 (d, J=8.30 Hz, 1H) 7.56 (d, J=1.22Hz, 1H) 7.72 (dd, J=8.27, 2.03 Hz, 1H) 8.76 (d, J=2.10 Hz, 1H) 9.43 (s,1H).

Furan-2-carboxylic acid[5-(1-methanesulfonyl-piperidin-4-ylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 58) was prepared as follows: Furan-2-carboxylic acid[5-(piperidin-4-ylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(0.35 g, 0.59 mmol) was stirred with a mixture of CH₂Cl₂ (5.0 mL) andTFA (3.0 mL) for 6 h. The reaction was concentrated to give theintermediate salt (0.225 g). The TFA salt of furan-2-carboxylic acid[5-(piperidin-4-ylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(0.06 g, 0.123 mmol) was dissolved in CH₂Cl₂ (5.0 mL) and DIPEA (0.2 mL,1.23 mmol) was added to this followed by acetic anhydride (0.062 g,0.615 mmol). The reaction mixture was stirred at room temperature for 1h. Reaction was concentrated and dissolved in methanol and purified onpreparative HPLC using MeOH/water as eluent to give the product (0.025g, 37%).

LCMS (ESI) 566 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (qd, J=11.93,3.69 Hz, 2H) 1.87 (d, J=10.74 Hz, 2H) 2.26 (s, 3H) 2.77-2.83 (m, 3H)2.84 (s, 3H) 3.04 (s, 8H) 3.54 (d, J=11.91 Hz, 2H) 6.70 (dd, J=3.47,1.76 Hz, 1H) 6.91-6.99 (m, 1H) 7.05-7.11 (m, 1H) 7.12-7.19 (m, 2H) 7.30(d, J=2.88 Hz, 1H) 7.35 (d, J=8.35 Hz, 1H) 7.61 (dd, J=8.30, 2.05 Hz,1H) 7.84-8.03 (m, 1H) 8.27 (d, J=7.76 Hz, 1H) 8.55 (d, J=2.00 Hz, 1H)9.42 (s, 1H).

Furan-2-carboxylic acid[5-[(S)-1-(4-chloro-phenyl)-2-methylamino-ethylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 55) was prepared following the same procedure as compoundno. 11 from the intermediate acid3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 570 (M−H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 2.32 (s, 3H)2.79 (s, 3H) 3.14 (s, 8H) 3.48-3.54 (m, 2H) 5.52 (dd, J=8.79, 5.86 Hz,1H) 6.67 (dd, J=3.47, 1.71 Hz, 1H) 6.91-7.03 (m, 1H) 7.12-7.20 (m, 3H)7.29 (d, J=3.47 Hz, 1H) 7.38-7.49 (m, 5H) 7.70 (dd, J=8.32, 2.03 Hz, 1H)7.81 (s, 1H) 8.71 (d, J=2.00 Hz, 1H).

Furan-2-carboxylic acid[5-(4-chloro-benzylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 131) was prepared following the same procedure as compoundno. 11 from the intermediate acid3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 529 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H) 3.04(s, 8H) 4.42 (d, J=5.76 Hz, 2H) 6.70 (dd, J=3.49, 1.68 Hz, 1H) 6.90-7.00(m, 1H) 7.06-7.11 (m, 1H) 7.13-7.19 (m, 2H) 7.26-7.40 (m, 6H) 7.66 (dd,J=8.35, 2.00 Hz, 1H) 7.98 (d, J=1.61 Hz, 1H) 8.61 (d, J=2.00 Hz, 1H)8.99 (t, J=6.08 Hz, 1H) 9.41 (s, 1H).

Furan-2-carboxylic acid[5-(3,5-dimethoxy-benzylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 95) was prepared following the same procedure as compoundno. 11 from the intermediate acid3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 555 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 2.39(s, 3H) 3.19 (d, J=9.71 Hz, 8H) 3.75-3.80 (m, 6H) 4.56 (d, J=5.81 Hz,2H) 6.38 (t, J=2.25 Hz, 1H) 6.51 (d, J=2.25 Hz, 2H) 6.56-6.63 (m, 2H)6.98-7.08 (m, 1H) 7.17-7.25 (m, 4H) 7.33-7.40 (m, 1H) 7.55-7.68 (m, 1H)8.87 (d, J=2.05 Hz, 1H) 9.44 (s, 1H).

Furan-2-carboxylic acid[5-(2-methoxy-benzylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 124) was prepared following the same procedure as compoundno. 11 from the intermediate acid3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 525 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 2.36(s, 3H) 3.11-3.22 (m, 9H) 3.88-3.92 (m, 3H) 4.60 (d, J=5.86 Hz, 2H) 6.60(dd, J=3.47, 1.76 Hz, 1H) 6.79 (t, J=5.54 Hz, 1H) 6.89-6.96 (m, 2H)6.99-7.06 (m, 1H) 7.12-7.38 (m, 6H) 7.55-7.64 (m, 2H) 8.82 (d, J=2.10Hz, 1H) 9.43 (brs, 1H).

Furan-2-carboxylic acid[5-[(naphthalen-1-ylmethyl)-carbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amideCompound no. 96) was prepared following the same procedure as compoundno. 11 from3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 545 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H) 3.04(s, 8H) 4.91 (d, J=5.66 Hz, 2H) 6.69 (dd, J=3.49, 1.73 Hz, 1H) 6.92-6.98(m, 1H) 7.05-7.11 (m, 1H) 7.15 (d, J=7.37 Hz, 2H) 7.29 (d, J=3.22 Hz,1H) 7.36 (d, J=8.35 Hz, 1H) 7.43-7.47 (m, 2H) 7.48-7.59 (m, 2H) 7.70(dd, J=8.35, 2.05 Hz, 1H) 7.82 (t, J=4.76 Hz, 1H) 7.90-7.94 (m, 1H) 7.98(d, J=1.12 Hz, 1H) 8.16 (d, J=8.10 Hz, 1H) 8.64 (d, J=2.05 Hz, 1H) 8.99(t, J=5.74 Hz, 1H) 9.41 (s, 1H).

Furan-2-carboxylic acid[5-((S)-2-hydroxy-1-phenyl-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 67) was prepared following the same procedure as compoundno. 11 from the intermediate acid3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 525 (M+H); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 2.35 (s, 3H)3.15 (s, 8H) 3.87 (d, J=6.59 Hz, 2H) 5.18-5.24 (m, 1H) 6.69 (dd, J=3.51,1.81 Hz, 1H) 6.95-7.02 (m, 1H) 7.17 (dd, J=3.73, 1.93 Hz, 3H) 7.24-7.29(m, 1H) 7.31 (d, J=3.51 Hz, 1H) 7.35 (t, J=7.57 Hz, 2H) 7.43 (dd,J=7.74, 3.25 Hz, 3H) 7.69 (d, J=2.15 Hz, 1H) 7.81-7.83 (m, 1H).

Furan-2-carboxylic acid[5-(3-methoxy-benzylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 93) was prepared following the same procedure as compoundno. 11 from the intermediate acid3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 525 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 2.45(s, 3H) 3.29 (d, J=10.20 Hz, 8H) 3.80 (s, 3H) 4.60 (d, J=5.76 Hz, 2H)6.56-6.63 (m, 2H) 6.80-6.86 (m, 1H) 6.88-6.99 (m, 2H) 7.05-7.14 (m, 1H)7.26 (dd, J=7.76, 2.44 Hz, 5H) 7.40 (s, 1H) 7.59-7.62 (m, 1H) 7.63-7.69(m, 1H) 8.86 (s, 1H) 9.41-9.49 (m, 1H).

Furan-2-carboxylic acid[2-(4-o-tolyl-piperazin-1-yl)-5-(4-trifluoromethyl-benzylcarbamoyl)-phenyl]-amide(compound no. 94) was prepared following the same procedure as compoundno. 11 from3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 525 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 2.41(s, 3H) 3.23 (d, J=9.57 Hz, 8H) 4.70 (d, J=5.91 Hz, 2H) 6.61 (dd,J=3.49, 1.78 Hz, 1H) 6.71-6.78 (m, 1H) 7.03-7.11 (m, 1H) 7.20-7.27 (m,4H) 7.38 (d, J=8.30 Hz, 1H) 7.51 (d, J=8.00 Hz, 2H) 7.59-7.65 (m, 3H)7.68 (dd, J=8.30, 2.10 Hz, 1H) 8.89 (d, J=2.05 Hz, 1H) 9.38-9.50 (m,1H).

2-Cyclopropyl-oxazole-4-carboxylic acid{2-[4-(3-methyl-pyridin-2-yl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amideLCMS (M+H) 572; ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 1.01-1.19 (m,4H) 1.75 (t, J=6.08 Hz, 2H) 1.98-2.12 (m, 4H) 2.33 (s, 3H) 2.38 (t,J=8.13 Hz, 2H) 3.06-3.13 (m, 4H) 3.32-3.45 (m, 9H) 6.90 (dd, J=7.30,4.91 Hz, 1H) 7.27 (d, J=8.25 Hz, 1H) 7.47 (d, J=6.83 Hz, 1H) 7.64 (dd,J=8.27, 2.07 Hz, 2H) 8.12 (s, 1H) 8.18 (dd, J=4.88, 1.46 Hz, 1H) 8.86(d, J=2.05 Hz, 1H) 9.90 (s, 1H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-{3-[(tetrahydro-pyran-4-carbonyl)-amino]-propylcarbamoyl}-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amideLCMS (M+H) 615; ¹H NMR (CHLOROFORM-d) δ ppm 9.99 (s, 1H), 8.89 (d, J=1.9Hz, 1H), 8.13 (s, 1H), 7.72 (dd, J=8.3, 2.0 Hz, 1H), 7.32 (d, J=8.2 Hz,1H), 7.20-7.26 (m, 2H), 7.15-7.20 (m, 1H), 7.02-7.09 (m, 1H), 6.78 (t,J=5.9 Hz, 1H), 6.70 (t, J=6.3 Hz, 1H), 4.05 (t, J=3.1 Hz, 1H), 4.01 (t,J=3.3 Hz, 1H), 3.53 (q, J=6.3 Hz, 2H), 3.40-3.48 (m, 2H), 3.33 (q, J=6.1Hz, 2H), 3.17-3.24 (m, 4H), 3.10-3.15 (m, 4H), 2.39-2.46 (m, 1H), 2.38(s, 3H), 2.07-2.15 (m, 1H), 1.79-1.92 (m, 4H), 1.70-1.78 (m, 2H),1.11-1.20 (m, 4H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-(3-propionylamino-propylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 559; ¹H NMR (CHLOROFORM-d) δ ppm 9.98 (s, 1H), 8.90 (d, J=1.9Hz, 1H), 8.13 (s, 1H), 7.72 (dd, J=8.2, 2.0 Hz, 1H), 7.31 (d, J=8.2 Hz,1H), 7.20-7.26 (m, 2H), 7.15-7.20 (m, 1H), 7.02-7.08 (m, 1H), 6.84 (t,J=5.7 Hz, 1H), 6.43-6.51 (m, 1H), 3.53 (q, J=6.2 Hz, 2H), 3.34 (q, J=6.2Hz, 2H), 3.17-3.23 (m, 4H), 3.09-3.16 (m, 4H), 2.38 (s, 3H), 2.28 (q,J=7.6 Hz, 2H), 2.06-2.15 (m, 1H), 1.75 (quin, J=6.0 Hz, 2H), 1.21 (t,J=7.6 Hz, 3H), 1.10-1.18 (m, 4H).

Furan-2-carboxylic acid[5-[3-(3-propyl-ureido)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 547; ¹H NMR (CHLOROFORM-d) δ ppm 9.48 (s, 1H), 8.88 (d, J=1.9Hz, 1H), 7.68-7.80 (m, 1H), 7.59 (s, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.24(d, J=4.9 Hz, 2H), 7.13 (d, J=7.7 Hz, 1H), 7.02-7.09 (m, 1H), 6.94-7.01(m, 1H), 5.16 (br. s., 1H), 4.64 (br. s., 1H), 3.57 (q, J=6.1 Hz, 2H),3.33 (q, J=5.9 Hz, 2H), 3.07-3.24 (m, 10H), 2.37 (s, 3H), 1.72-1.82 (m,2H), 1.52 (sxt, J=7.3 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H).

Furan-2-carboxylic acid[5-[3-(3-allyl-ureido)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 545; ¹H NMR (CHLOROFORM-d) δ ppm 9.48 (s, 1H), 8.89 (d, J=1.7Hz, 1H), 7.74 (dd, J=8.2, 1.9 Hz, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.24(d, J=4.6 Hz, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.01-7.09 (m, 1H), 6.93 (br.s., 1H), 6.52-6.67 (m, 1H), 5.77-5.96 (m, 1H), 5.15-5.33 (m, 2H), 5.10(d, J=10.2 Hz, 1H), 4.84 (br. s., 1H), 3.83 (t, J=5.6 Hz, 2H), 3.57 (q,J=5.9 Hz, 2H), 3.34 (q, J=5.9 Hz, 2H), 3.18 (d, J=5.0 Hz, 4H), 3.12 (br.s., 4H), 2.37 (s, 3H), 1.77 (br. s., 2H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-[3-(1H-tetrazol-5-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 556; ¹H NMR (CHLOROFORM-d) δ ppm 10.01 (br. s., 1H), 8.93 (s,1H), 8.16 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H),7.21-7.26 (m, 2H), 7.14-7.20 (m, 1H), 7.02-7.10 (m, 1H), 3.55 (d, J=5.6Hz, 2H), 3.21 (d, J=4.0 Hz, 4H), 3.15 (d, J=3.8 Hz, 4H), 3.07-3.12 (m,2H), 2.38 (s, 3H), 2.08-2.18 (m, 1H), 2.02 (br. s., 2H), 1.10-1.24 (m,4H).

Furan-2-carboxylic acid[5-[(6-dimethylamino-methyl-pyridin-2-ylmethyl)-carbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 553; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm: 2.35 (s, 3H) 2.97(s, 6H) 3.17 (s, 8H) 3.34-3.39 (m, 1H) 4.46 (s, 2H) 4.76 (s, 2H)6.64-6.74 (m, 1H) 6.94-7.04 (m, 1H) 7.12-7.23 (m, 3H) 7.29-7.33 (m, 1H)7.35-7.40 (m, 1H) 7.43-7.51 (m, 2H) 7.69-7.77 (m, 1H) 7.81-7.85 (m, 1H)7.86-7.93 (m, 1H) 8.75-8.85 (m, 1H).

Furan-2-carboxylic acid[5-[3-((1R,4S)-5,6-dihydroxy-3-oxo-2-aza-bicyclo[2.2.1]hept-2-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 588; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.77-1.91 (m, 2H)1.91-1.99 (m, 1H) 2.06-2.14 (m, 1H) 2.35 (s, 3H) 2.54-2.62 (m, 1H)2.99-3.10 (m, 1H) 3.33-3.39 (m, 1H) 3.40-3.51 (m, 2H) 3.65-3.81 (m, 1H)3.97 (d, J=1.61 Hz, 2H) 6.63-6.75 (m, 1H) 6.92-7.07 (m, 1H) 7.09-7.24(m, 3H) 7.27-7.35 (m, 1H) 7.37-7.51 (m, 1H) 7.61-7.71 (m, 1H) 7.74-7.94(m, 1H) 8.65-8.77 (m, 1H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-[3-(2-hydroxy-ethylcarbamoyl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 575; ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 0.99-1.22 (m,4H) 1.94 (d, J=8.88 Hz, 2H) 2.05-2.17 (m, 1H) 2.22-2.31 (m, 2H) 2.35 (s,3H) 3.06-3.22 (m, 8H) 3.38 (d, J=4.34 Hz, 2H) 3.48 (d, J=6.25 Hz, 2H)3.60-3.72 (m, 1H) 6.53-6.64 (m, 1H) 6.81-6.94 (m, 1H) 6.97-7.05 (m, 1H)7.13-7.24 (m, 3H) 7.31 (d, J=8.30 Hz, 1H) 7.60 (d, J=2.15 Hz, 1H) 8.13(s, 1H) 8.82 (d, J=2.10 Hz, 1H) 9.86-10.05 (m, 1H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-[3-(3-methyl-2-oxo-imidazolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 586; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.12 (d, J=6.59 Hz,4H) 1.71-1.88 (m, 2H) 2.06-2.20 (m, 1H) 2.35 (s, 3H) 2.73 (s, 3H)3.06-3.15 (m, 4H) 3.17-3.26 (m, 5H) 3.30-3.44 (m, 6H) 6.90-7.06 (m, 1H)7.09-7.25 (m, 3H) 7.33-7.45 (m, 1H) 7.53-7.67 (m, 1H) 8.16-8.39 (m, 1H)8.63-8.96 (m, 1H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-[3-(acetyl-methyl-amino)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS (M+H) 559; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.92 (1H, s) 8.81 (1H,d, J=1.81 Hz) 8.68 (1H, s) 8.35-8.50 (1H, m) 7.56-7.63 (1H, m) 7.42 (1H,d, J=8.25 Hz) 7.18-7.25 (2H, m) 7.11-7.16 (1H, m) 7.01 (1H, t, J=7.27Hz) 3.34 (2H, br. s.) 3.19-3.29 (2H, m) 3.11 (4H, d, J=4.59 Hz) 3.05(4H, br. s.) 2.96 (2H, s) 2.79 (1H, s) 2.31 (3H, s) 2.15-2.24 (1H, m)1.98 (3H, d, J=3.51 Hz) 1.75-1.84 (1H, m) 1.69 (1H, quin, J=6.97 Hz)1.10-1.17 (2H, m) 1.03-1.09 (2H, m).

N-(5-((3-((ethyl(methyl)amino)methyl)benzyl)-carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)furan-2-carboxamide

LC/MS-ESI: [M+1] 566.33; NMR (DMSO-d₆) b 9.44 (s, 1, NH—CO), 9.03 (t, 1,CON—H), 8.64 (d, 1, Furan-H), 8.01 (dd, 1, Ar—H), 7.70 (dd, 1, Ar—H),7.36-7.44 (m, 5, 5×Ar-H), 7.31 (d, 1, Furan-H), 7.18 (t, 2, 2×Ar-H),7.11 (d, 1, Ar—H), 6.98 (t, 1, Furan-H), 6.72 (dd, 1, Ar—H), 4.50 (d, 2,CON—CH₂), 4.35 (dd, 1, NC—H), 4.19 (dd, 1, NC—H), 3.00-3.16 (m, 10,2×CH₂CH₂, NCH₂), 2.64 (d, 3, NCH₃), 2.28 (s, 3, Ar—CH₃), 1.19 (t, 3,3×CH₂CH₂—H).

N-(5-((3-sulfamoylbenzoyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)furan-2-carboxamide

LC/MS-ESI: [M+1] 574.36; NMR (DMSO-d₆) b 9.48 (s, 1, CON—H), 9.15 (t, 1,CON—H), 8.68 (s, 1, Furan-H), 8.04 (s, 1, Ar—H), 7.81 (s, 1, Ar—H), 7.74(m, 2, 2×Ar-H), 7.55 (m, 2, 2×Ar-H), 7.43 (d, 1, Ar—H), 7.33-7.39 (m, 3,2×Ar-H, Furan-H), 7.14 (d, 1, Ar—H), 7.01 (t, 1, Furan-H), 6.75 (m, 1,Ar—H), 4.57 (d, 2, CON—CH2), 3.10 (m, 8, 8×CH₂CH₂), 2.31 (s, 3, Ar—CH₃)

(R)—N-(5-((2-hydroxy-2-phenylethyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)furan-2-carboxamide

LC/MS-ESI: [M+1] 525.3; NMR (DMSO-d₆) b 9.45 (s, 1, CON—H), 8.62 (d, 1,Furan-H), 8.43 (t, 1, CON—H), 8.03 (d, 1, Ar—H), 7.66 (dd, 1, Ar—H),7.31-7.43 (m, 6, Furan-H, 5×Ar-H), 7.17-7.30 (m, 3, 3×Ar-H), 7.14 (d, 1,Ar—H) 6.98 (t, 1, Furan-H), 6.75 (dd, 1, Ar—H), 5.51 (d, 1, HO—CH), 4.80(m, 1, O—H), 3.42-3.56 (m, 1, CONC—H), 3.22-3.42 (m, 1, CONC—H), 3.09(s, 8, 2×CH₂CH₂), 2.92 (s, 3, Ar—CH₃).

N-(5-((2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)furan-2-carboxamide

LC/MS-ESI: [M+1] 530.20; NMR (DMSO-d₆) δ 9.43 (s, 1, CON—H), 8.54 (d, 1,Furan-H), 8.46 (t, 1, CON—H), 8.01 (m, 1, Ar—H), 7.53 (dd, 1, Ar—H),7.37 (d, 1, Ar—H), 7.32 (d, 1, Furan-H), 7.18 (d, 2, 2×Ar-H), 7.12 (d,1, Ar—H), 6.98 (t, 1, Furan-H), 6.72 (dd, 1, Ar—H), 3.53 (t, 2,CON—CH₂), 3.39 (m, 2, CON—CH₂), 3.07 (s, 8, 2×CH₂CH₂), 2.58 (s, 4,2×COCH₂), 2.29 (s, 3, Ar—CH₃).

3-((furan-2-ylmethyl)amino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(4-(o-tolyl)piperazin-1-yl)benzamide

LC/MS-ESI: [M+1] 516.00; NMR (DMSO-d₆) δ 8.21 (t, 1, CON—H), 7.59 (s, 1,Furan-H), 7.05-7.25 (m, 6, Ar—H) 7.02 (t, 1, Ar—H), 6.39 (t, 1,Furan-H), 6.29 (d, 1, Furan-H), 4.43 (s, 2, Furan-CH₂), 3.35 (t, 2,CON—CH₂), 3.14-3.28 (m, 4, CON—CH₂, CON—CH₂), 3.08 (s, 4, CH₂CH₂), 3.02(s, 4, CH₂CH₂), 2.31 (s, 3, Ar—CH₃), 2.24 (t, 2, CO—CH₂), 1.91 (m, 2,CH₂), 1.69 (m, 2, CH₂).

N-(5-((3-carbamoylbenzyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)-2-cyclopropyloxazole-4-carboxamide

LC/MS-ESI: [M+1] 579.37; NMR (DMSO-d₆) δ 9.91 (s, 1, CON—H), 9.04 (t, 1,CON—H), 8.85 (d, 1, Ar—H), 8.67 (d, 1, Oxazole-H), 7.95 (s, 1, CON—H),7.82 (s, 1, Ar—H), 7.73 (d, 1, Ar—H), 7.68 (dd, 1, Ar—H), 7.37-7.46(ddd, 3, 3×Ar-H), 7.32 (s, 1, CON—H), 7.16-7.24 (m, 2, 2×Ar-H), 7.13 (d,1, Ar—H), 7.00 (t, 1, Ar—H), 4.50 (d, 2, CON—CH₂), 3.10-3.04 (m, 8,2×CH2CH2), 2.30 (s, 3, Ar—CH₃), 2.18 (m, 1, CH), 1.01-1.14 (m, 4,2×CH₂).

2-cyclopropyl-N-(5-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)oxazole-4-carboxamide

LC/MS-ESI: [M+1] 576.02; NMR (DMSO-d₆) δ 9.85 (s, 1, CON—H), 8.73 (d, 1,CO—NH), 8.60 (s, 1, Oxazole-H), 8.18 (d, 1, Ar—H), 7.53 (d, 1, Ar—H),7.34 (t, 1, Ar—H), 7.12 (m, 2, 2×Ar-H), 7.09 (d, 1, Ar—H) 6.93 (t, 1,Ar—H), 4.09 (t, 1, OC—H), 3.69 (dq, 2, OC—H), 3.37 (m, 2, OCH₂),2.96-3.05 (m, 8, 2×CH₂CH₂), 2.25 (s, 3, Ar—CH₃), 1.75-2.13 (m, 4, OC—H,CH, CH₂), 0.7-1.09 (m, 5, CH₂, CH₂, CH—H).

2-cyclopropyl-N-(5-(((1R,2S,3R)-2,3-dihydroxycyclohexyl)-carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)oxazole-4-carboxamidetrifluoroacetate

LC/MS-ESI: [M+1] 560.21; NMR (DMSO-d₆) δ 9.86 (s, 1, CON—H), 8.72 (s, 1,CON—H), 8.60 (s, 1, Oxazole-H), 7.94 (d, 1, Ar—H), 7.56 (d, 1, Ar—H),7.34 (s, 1, Ar—H), 7.15 (d, 2, 2×Ar-H), 7.09 (d, 1, Ar—H), 6.93 (t, 1,Ar—H), 4.00 (dd, 1, OC—H), 3.80 (s, 1, CON—CH), 3.37 (d, 1, OC—H), 3.04(s, 4, CH₂CH₂), 2.99 (s, 4, CH₂CH₂), 2.25 (s, 3, Ar—CH₃), 2.13 (m, 1,OC—H, CH, CH₂), 1.01-1.71 (m, 11, 5×CH₂, 5×CH₂, C—H).

2-cyclopropyl-N-(5-(((1R,2S,3R)-2,3-dihydroxy-cyclohexyl)-carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)oxazole-4-carboxamidehydrochloride

LC/MS-ESI: [M+1] 560.21; NMR (DMSO-d₆) δ 9.93 (s, 1, CON—H), 8.79 (s, 1,CON—H), 8.68 (s, 1, Oxazole-H), 8.02 (d, 1, Ar—H), 7.66 (d, 1, Ar—H),7.41 (d, 1, Ar—H), 7.10-7.30 (m, 3, 3×Ar-H), 7.03 (t, 1, Ar—H), 4.06(tq, 1, OC—H), 3.87 (s, 1, CON—CH), 3.44 (dd, 1, OC—H), 3.14 (s, 4,CH₂CH₂), 3.08 (s, 4, CH₂CH₂), 2.51 (s, 3, Ar—CH₃), 2.20 (m, 1, CH),1.19-1.89 (m, 6, 6×CH₂), 1.00-1.19 (m, 4, CH₂CH₂).

2-cyclopropyl-N-(5-(((1S,2R,3S)-2,3-dihydroxycyclohexyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)oxazole-4-carboxamide

LC/MS-ESI: [M+1] 560.07; NMR (DMSO-d6) δ 9.93 (s, 1, CON—H), 8.79 (s, 1,CON—H), 8.68 (s, 1, Oxazole-H), 8.02 (d, 1, Ar—H), 7.66 (d, 1, Ar—H),7.41 (d, 1, Ar—H), 7.10-7.30 (m, 3, 3×Ar-H), 7.03 (t, 1, Ar—H), 4.06(tq, 1, OC—H), 3.87 (s, 1, CON—CH), 3.44 (dd, 1, OC—H), 3.14 (s, 4,CH₂CH₂), 3.08 (s, 4, CH₂CH₂), 2.51 (s, 3, Ar—CH₃), 2.20 (m, 1, CH),1.19-1.89 (m, 6, 6×CH₂), 1.00-1.19 (m, 4, CH₂CH₂).

2-cyclopropyl-N-(5-(((1R,3S)-3-hydroxycyclohexyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)oxazole-4-carboxamide

LC/MS-ESI: [M+1] 544.09; NMR (DMSO-d₆) δ 9.93 (s, 1, CON—H), 8.79 (d, 1,CON—H), 8.67 (s, 1, Oxazole-H), 8.24 (d, 1, Ar—H), 7.60 (dd, 1, Ar—H),7.41 (d, 1, Ar—H), 7.10-7.30 (m, 3, 3×Ar-H), 7.02 (m, 1, Ar—H), 4.06(tq, 1, OC—H), 3.24-4.11 (broad, 3) 3.12 (d, 4, CH₂CH₂), 3.06 (d, 4,CH₂CH₂), 2.32 (s, 3, Ar—CH₃), 2.21 (m, 1, CH), 2.03 (m, 1, CH),1.63-1.89 (m, 3, 3×CH₂), 1.00-1.37 (m, 8, 2×CH₂CH₂).

2-cyclopropyl-N-(5-(((1R,3R)-3-hydroxycyclohexyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)oxazole-4-carboxamide

LC/MS-ESI: [M+1] 544.19; NMR (DMSO-d₆) δ 9.93 (s, 1, CON—H), 8.77 (d, 1,CON—H), 8.67 (s, 1, Oxazole-H), 8.06 (d, 1, Ar—H), 7.59 (dd, 1, Ar—H),7.40 (d, 1, Ar—H), 7.10-7.30 (m, 3, 3×Ar-H), 7.02 (m, 1, Ar—H), 4.19 (m,1), 3.93 (d, 1, OC—H), 3.23-3.84 (broad), 3.12 (d, 4, CH₂CH₂), 3.05 (d,4, CH₂CH₂), 2.32 (s, 3, Ar—CH₃), 2.21 (m, 1, CH), 1.19-1.83 (m, 8,2×CH₂CH₂), 1.00-1.19 (m, 4, CH₂CH₂).

2-cyclopropyl-N-(5-((3-hydroxycyclohexyl)carbamoyl)-2-(4-(o-tolyl)piperazin-1-yl)phenyl)oxazole-4-carboxamide

LC/MS-ESI: [M+1] 544.40; NMR (DMSO-d₆) δ 9.85 (s, 1, CON—H), 8.71 (d, 1,CO—NH), 8.60 (s, 1, Oxazole-H), 8.16 (dd, 0.46, Ar—H), 7.98 (dd, 0.68,Ar—H), 7.47-7.56 (m, 1, Ar—H), 7.28-7.37 (m, 1, Ar—H), 7.04-7.20 (m, 3,3×Ar-H), 6.93 (m, 1, Ar—H), 4.06 (tq, 1, OC—H), 3.24-4.11 (broad, 3)3.12 (d, 4, CH₂CH₂), 3.06 (d, 4, CH₂CH₂), 2.25 (s, 3, Ar—CH₃), 2.13 (m,1, CH), 0.91-1.98 (m, 12, 3×CH₂CH₂).

Furan-2-carboxylic acid[5-[3-(4-hydroxy-phenyl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS: (Method A) 539.2 (M+H), Rt 4.8 min, 96.7% (Max), 97.4% (254 nm).

¹H NMR 400 MHz, CDCl₃: δ 9.48 (s, 1H), 8.68 (s, 1H), 7.78 (d, J=4.00 Hz,1H), 7.60 (s, 1H), 7.33 (d, J=8.00 Hz, 1H), 7.30 (t, J=4.00 Hz, 1H),7.24 (d, J=8.00 Hz, 2H), 7.13 (d, J=8.00 Hz, 1H), 7.04-7.06 (m, 3H),6.80 (d, J=8.00 Hz, 2H), 6.61-6.62 (m, 1H), 6.53 (s, 1H), 5.83 (s, 1H),3.46-3.51 (m, 2H), 3.12-3.18 (m, 8H), 2.67 (t, J=4.00 Hz, 2H), 2.37 (s,3H), 1.91-1.94 (m, 2H).

Furan-2-carboxylic acid[5-[2-hydroxy-3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS: (Method A) 546.3 (M+H), Rt 3.8 min, 97.3% (Max), 98.8% (254 nm).

¹H NMR 400 MHz, CDCl₃: (9.42 (s, 1H), 8.98 (d, J=4.00 Hz, 1H), 7.73 (d,J=12.00 Hz, 1H), 7.53-7.57 (m, 2H), 7.32 (d, J=8.00 Hz, 1H), 7.28 (s,1H), 7.23-7.26 (m, 2H), 7.13 (d, J=8.00 Hz, 1H), 7.06-7.08 (m, 1H), 6.60(d, J=4.00 Hz, 1H), 4.30 (d, J=8.00 Hz, 1H), 4.01-4.02 (m, 1H),3.73-3.79 (m, 1H), 3.50-3.60 (m, 3H), 3.33-3.43 (m, 2H), 3.17-3.18 (m,4H), 3.12-3.14 (m, 4H), 2.46 (t, J=8.00 Hz, 2H), 2.37 (s, 3H), 2.05-2.12(m, 2H).

Furan-2-carboxylic acid[5-[3-(2-oxo-imidazolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

LCMS: (Method A) 531.2 (M+H), Rt 3.9 min, 95.0% (Max). 93.5% (254 nm);

¹H NMR 400 MHz, CDCl₃: δ 9.46 (s, 1H), 8.88 (s, 1H), 7.76 (d, J=8.00 Hz,1H), 7.57 (s, 1H), 7.53 (t, J=4.00 Hz, 1H), 7.31 (d, J=8.00 Hz, 2H),7.23-7.34 (m, 2H), 7.13 (d, J=8.00 Hz, 1H), 7.04-7.07 (m, 1H), 6.59 (s,1H), 3.47-3.50 (m, 6H), 3.34-3.37 (m, 2H), 3.17-3.18 (m, 4H), 3.11-3.13(m, 4H), 2.37 (s, 3H), 1.80-1.83 (m, 2H).

2-Cyclopropyl-oxazole-4-carboxylic acid{2-[4-(3-chloro-pyridin-2-yl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide

LCMS: (Method A) 592.3 (M+H), Rt 4.4 min, 95.4% (Max). 96.4% (254 nm);

¹H NMR 400 MHz, CDCl₃: δ 9.94 (s, 1H), 8.97 (d, J=4.00 Hz, 1H),8.23-8.25 (m, 1H), 8.13 (s, 1H), 7.73 (d, J=8.00 Hz, 1H), 7.65 (s, 1H),7.58-7.63 (m, 1H), 7.26 (s, 1H), 6.88-6.91 (m, 1H), 3.65-3.67 (m, 4H),3.40-3.45 (m, 6H), 3.11-3.13 (m, 4H), 2.44-2.48 (m, 2H), 2.03-2.11 (m,3H), 1.81-1.84 (m, 2H), 1.14-1.18 (m, 2H), 1.08-1.09 (m, 2H).

The preparation of all compounds depicted in Table 2 was in line withScheme 1.

Example 2 Synthetic route towards(R)-3-[3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-piperidine-1-carboxylicacid ethylamide (compound no. 48)

Step 1

The compound was prepared in a similar fashion to compound no. 11 from3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

Step 2

(R)-3-[3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-piperidine-1-carboxylicacid tert-butyl ester (0.12 g, 0.204 mmol) was stirred with a mixture ofDCM (1.0 mL) and TFA (1.0 mL) for 4 h. LC-MS indicated the completion ofdeprotection. The mixture was concentrated and dissolved in pyridine(5.0 mL). EtNCO (29 mg, 0.41 mmol) was added and the reaction mixturewas stirred at 45° C. for 6 h. Pyridine was rotavaped out and the crudewas dissolved in methanol and purified on preparatory HPLC usingwater/methanol as eluent to give desired product (0.02 g, 18%).

LCMS (ESI) 559 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.05-1.13 (m,3H) 1.50-1.68 (m, 2H) 1.73-1.81 (m, 1H) 1.96-2.08 (m, 1H) 2.32 (s, 3H)2.78-2.96 (m, 2H) 3.12 (s, 9H) 3.17 (q, J=7.19 Hz, 3H) 3.77-4.00 (m, 3H)6.66 (dd, J=3.51, 1.76 Hz, 1H) 6.96 (td, J=7.11, 1.73 Hz, 1H) 7.08-7.19(m, 3H) 7.28 (d, J=3.47 Hz, 1H) 7.38 (d, J=8.35 Hz, 1H) 7.61 (dd,J=8.30, 2.10 Hz, 1H) 7.79 (d, J=1.07 Hz, 1H) 8.63 (d, J=2.05 Hz, 1H).

The preparation of following compounds was in line with Scheme 2:

{2-[3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-ethyl}-methyl-carbamicacid tert-butyl ester (compound no. 64) was prepared comprising the sameprocedure as compound no. 11 from3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

LCMS (ESI) 562 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.40(s, 9H) 1.54-1.64 (m, 1H) 2.36 (s, 3H) 2.89 (brs, 3H) 3.15 (dd, J=17.01,5.59 Hz, 8H) 3.48 (brs, 2H) 3.52-3.60 (m, 2H) 6.60 (dd, J=3.39, 1.73 Hz,1H) 6.97-7.05 (m, 1H) 7.12-7.25 (m, 4H) 7.31 (brs, 1H) 7.56 (brs., 1H)7.60 (s, 1H) 8.83 (d, J=2.00 Hz, 1H) 9.24-9.52 (m, 1H).

Furan-2-carboxylic acid[5-(2-methylamino-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 132) was prepared as follows: {2-[3-[(Furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-ethyl}-methyl-carbamicacid tert-butyl ester (0.1 g, 0.17 mmol) was stirred with a mixture ofDCM (2.0 mL) and TFA (2.0 mL) for 2 h. Reaction was concentrated to give0.07 g of the TFA salt.

LCMS (ESI) 462 (M+H); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 2.33 (s, 3H)2.74 (s, 3H) 3.12-3.19 (m, 8H) 3.23 (t, J=5.66 Hz, 2H) 3.68 (t, J=5.66Hz, 2H) 6.67 (dd, J=3.54, 1.78 Hz, 1H) 6.94-7.02 (m, 1H) 7.12-7.20 (m,3H) 7.29 (d, J=2.98 Hz, 1H) 7.41 (d, J=8.35 Hz, 1H) 7.68 (dd, J=8.35,2.15 Hz, 1H) 7.80 (d, J=1.02 Hz, 1H) 8.72 (d, J=2.10 Hz, 1H).

Furan-2-carboxylic acid[5-{2-[(2,2-dimethyl-butyryl)-methyl-amino]-ethylcarbamoyl}-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 133) was prepared as follows: To a solution offuran-2-carboxylic acid[5-(2-methylamino-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(0.04 g, 0.086 mmol) and diisopropylethylamine (0.5 mL) in CH₂Cl₂ (2.0mL), 2,2-dimethyl butyryl chloride (0.173 mmol) was added at 0° C., andthe reaction was stirred at 0-25° C. for 4 h. Reaction was diluted withCH₂Cl₂ and washed with a solution of saturated NaHCO₃. Organic layer wasconcentrated and dissolved in ACN and purified on preparative HPLC usingwater/MeOH (0.1% TFA) as eluent to give the product (0.01 g, 21% yield).

LCMS (ESI) 560 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 0.81(t, J=7.49 Hz, 3H) 1.22 (s, 6H) 1.59-1.69 (m, 2H) 2.34 (s, 3H) 3.06-3.19(m, 11H) 3.54-3.67 (m, 4H) 6.59 (dd, J=3.47, 1.76 Hz, 1H) 7.00 (td,J=7.33, 1.24 Hz, 1H) 7.11-7.15 (m, 1H) 7.17-7.25 (m, 3H) 7.29 (s, 1H)7.35 (brs, 1H) 7.51 (dd, J=8.27, 2.07 Hz, 1H) 7.57-7.64 (m, 1H) 8.81 (d,J=2.05 Hz, 1H) 9.38 (s, 1H).

Benzo[1,3]dioxole-5-carboxylic acid{2-[3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-ethyl}-methyl-amide(compound no. 134) was prepared following the same procedure asfuran-2-carboxylic acid[5-{2-[(2,2-dimethyl-butyryl)-methyl-amino]-ethylcarbamoyl}-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amideusing piperanoyl chloride.

LCMS (ESI) 610 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) S ppm 2.34(s, 3H) 3.06 (s, 3H) 3.09-3.19 (m, 8H) 3.68 (brs, 4H) 5.98 (s, 2H) 6.60(dd, J=3.47, 1.76 Hz, 1H) 6.80 (d, J=7.91 Hz, 1H) 6.89-6.96 (m, 1H)6.97-7.04 (m, 2H) 7.08-7.15 (m, 1H) 7.20 (dd, J=6.83, 5.56 Hz, 2H) 7.25(d, J=3.42 Hz, 1H) 7.33 (d, J=8.30 Hz, 1H) 7.48-7.56 (m, 1H) 7.57-7.62(m, 2H) 8.70-8.97 (m, 1H) 9.41 (s, 1H).

Example 3 Synthetic route towards4-[3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-piperidine-1-carboxylicacid tert-butyl ester (compound no. 175)

Step 1

3-Nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (1.0 g, 2.9 mmol) wastaken in methanol (100 mL) with sulphuric acid (1.0 mL) and reflux for16 h. Concentrated and dissolved in ethyl acetate (300 mL) and washedthe organic layer with a solution of satd. NaHCO₃, dried andconcentrated to give 0.37 g of3-Nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester.

Step 2

The same procedure was applied in the preparation of3-amino-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid.

Step 3 and STEP 4

3-amino-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester (2.0 g,6.15 mmol) in CH₂Cl₂ (50 mL) was added triethylamine (1.7 mL, 12.3 mmol)and cooled to 0° C. 5-Methyl furoyl chloride (1.06 g, 7.38 mmol) inCH₂Cl₂ (5.0 mL) was added drop wise and the reaction was stirred at0-25° C. for 6 h. Reaction was diluted CH₂Cl₂ (100 mL) and washed with asolution of saturated NaHCO₃, dried and concentrated to give the crudeproduct, which was dissolved in a mixture of MeOH (60 mL) and THF (60mL) and stirred with a solution of LiOH.H₂O (2.17 g, 53 mmol) in water(20 mL) for 6 h. The solvents were removed and the contents weredissolved in water and acidified to pH 5.0 using 2 N HCl. The3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid was filtered and dried (1.37 g, 64%).

Step 5

This was prepared from acid intermediate3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid and 4-Amino-piperidine-1-carboxylic acid tert-butyl ester followingthe EDC amidation procedure described in the preparation of compound no.11.

LCMS (ESI) 602 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.41-1.46 (m, 9H) 1.94-2.03 (m, 2H) 2.36 (s, 3H) 2.43 (s, 3H) 2.81-2.96(m, 2H) 3.15 (dd, J=15.89, 5.74 Hz, 8H) 4.01-4.16 (m, 3H) 6.07-6.26 (m,2H) 6.94-7.06 (m, 1H) 7.09-7.14 (m, 2H) 7.16-7.25 (m, 2H) 7.32 (d,J=8.25 Hz, 1H) 7.58 (dd, J=8.25, 2.15 Hz, 1H) 8.78 (d, J=2.10 Hz, 1H)9.46 (s, 1H).

The preparation of following compounds was in line with Scheme 3:

5-Methyl-furan-2-carboxylic acid[5-[2-(1H-imidazol-4-yl)-ethylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 185) was prepared comprising the same procedure ascompound no. 11 from the intermediate acid3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 513 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.76(t, J=6.03 Hz, 2H) 1.99-2.09 (m, 2H) 2.36-2.43 (m, 5H) 3.10-3.15 (m, 4H)3.25-3.44 (m, 10H) 3.87 (s, 3H) 6.20 (dd, J=3.37, 0.98 Hz, 1H) 6.89-7.05(m, 4H) 7.11 (d, J=3.32 Hz, 1H) 7.33 (d, J=8.25 Hz, 1H) 7.64 (dd,J=8.25, 2.10 Hz, 2H) 8.87 (d, J=2.10 Hz, 1H) 9.46 (s, 1H).

5-Methyl-furan-2-carboxylic acid[5-(3,4-dimethoxy-benzylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 171) was prepared comprising the same procedure ascompound no. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 569 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 2.35 (s, 3H)2.45 (s, 3H) 3.08-3.21 (m, 8H) 3.82 (d, J=8.25 Hz, 6H) 4.52 (s, 2H) 6.31(dd, J=3.42, 0.93 Hz, 1H) 6.91-6.93 (m, 2H) 6.97-7.02 (m, 2H) 7.12-7.21(m, 4H) 7.41 (d, J=8.30 Hz, 1H) 7.65 (dd, J=8.30, 2.15 Hz, 1H) 8.74 (d,J=2.10 Hz, 1H).

5-Methyl-furan-2-carboxylic acid [5-[2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)ethylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 174) was prepared comprising the same procedure ascompound no. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 580 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 2.35 (s, 3H)2.45 (s, 3H) 2.77 (t, J=6.35 Hz, 2H) 3.05-3.20 (m, 16H) 3.52 (t, J=6.30Hz, 2H) 6.31 (dd, J=3.42, 0.98 Hz, 1H) 6.96-7.01 (m, 1H) 7.12-7.21 (m,4H) 7.42 (d, J=8.30 Hz, 1H) 7.61 (d, J=2.15 Hz, 1H) 8.74 (d, J=2.10 Hz,1H).

5-Methyl-furan-2-carboxylic acid [5-{[4-(4-methoxy-phenyl)-1H-pyrazol-3-ylmethyl]-carbamoyl}-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 172) was prepared comprising the same procedure ascompound no. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 605 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 2.32-2.37 (m,3H) 2.45 (s, 3H) 3.15 (q, J=5.81 Hz, 8H) 3.79-3.84 (m, 3H) 4.58 (s, 2H)6.31 (dd, J=3.42, 0.93 Hz, 1H) 6.94-7.06 (m, 4H) 7.12-7.21 (m, 4H) 7.38(d, J=8.30 Hz, 1H) 7.51-7.60 (m, 3H) 8.62 (d, J=2.05 Hz, 1H).

5-Methyl-furan-2-carboxylic acid[5-cyclopropylcarbamoyl-2-(4-o-tolyl-piperazin-1-yl)-phenyl]amide(compound no. 195) was prepared comprising the same procedure ascompound no. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 459 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm0.55-0.64 (m, 2H) 0.77-0.86 (m, 2H) 2.41 (d, J=12.30 Hz, 6H) 2.79-2.91(m, 1H) 3.09-3.27 (m, 8H) 6.21 (dd, J=3.37, 0.98 Hz, 1H) 6.35 (s, 1H)7.01-7.07 (m, 1H) 7.10-7.26 (m, 4H) 7.33 (d, J=8.30 Hz, 1H) 7.57 (dd,J=8.25, 2.10 Hz, 1H) 8.74 (d, J=2.05 Hz, 1H) 9.45 (brs, 1H).

(R)-3-[3-[(5-Methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (compound no. 142) was prepared comprising thesame procedure as compound no. 11 from the intermediate acid3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 588 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 1.44(s, 9H) 1.81-2.00 (m, 1H) 2.23 (dq, J=13.47, 6.54 Hz, 1H) 2.35 (s, 3H)2.43 (s, 3H) 3.07-3.17 (m, 8H) 3.18-3.32 (m, 1H) 3.37-3.51 (m, 2H)3.64-3.77 (m, 1H) 4.49-4.70 (m, 1H) 6.20 (dd, J=3.37, 0.98 Hz, 1H) 6.46(d, J=11.37 Hz, 1H) 6.93-7.04 (m, 1H) 7.07-7.13 (m, 2H) 7.14-7.25 (m,2H) 7.31 (d, J=8.25 Hz, 1H) 7.57 (dd, J=8.22, 2.12 Hz, 1H) 8.78 (d,J=1.90 Hz, 1H) 9.45 (s, 1H).

5-Methyl-furan-2-carboxylic acid[5-[(pyridin-3-ylmethyl)-carbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 218) was prepared comprising the same procedure ascompound no. 11 using3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 510 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 2.36(s, 3H) 2.44 (s, 3H) 3.09-3.20 (m, 8H) 4.70 (d, J=5.86 Hz, 2H) 6.21 (d,J=2.68 Hz, 1H) 6.95-7.06 (m, 2H) 7.11 (d, J=3.66 Hz, 2H) 7.20 (t, J=8.35Hz, 2H) 7.35 (d, J=8.30 Hz, 1H) 7.51 (brs, 1H) 7.67 (dd, J=8.25, 2.00Hz, 1H) 8.01 (d, J=7.91 Hz, 1H) 8.52-8.75 (m, 2H) 8.88 (d, J=1.95 Hz,1H) 9.46 (brs, 1H).

5-Methyl-furan-2-carboxylic acid[5-(3-imidazol-1-yl-propylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 210) was prepared comprising the same procedure ascompound no. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 527 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.14 (quin,J=6.80 Hz, 2H) 2.38 (s, 3H) 2.45 (s, 3H) 3.16 (dd, J=16.08, 4.95 Hz, 8H)3.50 (q, J=6.52 Hz, 2H) 4.07 (t, J=7.05 Hz, 2H) 6.22 (d, J=2.64 Hz, 1H)6.59 (t, J=5.30 Hz, 1H) 6.96-7.13 (m, 5H) 7.15-7.22 (m, 2H) 7.35 (d,J=8.25 Hz, 1H) 7.52-7.58 (m, 1H) 7.76 (dd, J=8.27, 1.73 Hz, 1H) 8.81 (d,J=1.61 Hz, 1H) 9.51 (s, 1H).

5-Methyl-furan-2-carboxylic acid[5-(3-hydroxy-propylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amidewas prepared comprising the same procedure as compound no. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 477 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.69-1.81 (m, 2H) 2.35 (s, 3H) 2.43 (s, 3H) 3.08-3.21 (m, 8H) 3.52-3.69(m, 4H) 6.21 (d, J=2.59 Hz, 1H) 6.71-6.83 (m, 1H) 6.91-7.04 (m, 1H)7.07-7.13 (m, 2H) 7.16-7.25 (m, 2H) 7.33 (d, J=8.30 Hz, 1H) 7.64 (dd,J=8.27, 2.07 Hz, 1H) 8.83 (d, J=1.66 Hz, 1H) 9.26-9.58 (m, 1H).

5-Methyl-furan-2-carboxylic acid[5-(4-hydroxy-butylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 241) was prepared comprising the same procedure ascompound no. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 491 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.72-1.85 (m,4H) 2.38 (s, 3H) 2.45 (s, 3H) 3.00 (brs, 1H) 3.15 (dd, J=17.16, 5.49 Hz,8H) 3.50 (q, J=5.63 Hz, 2H) 3.81-3.88 (m, 2H) 6.21 (d, J=2.64 Hz, 1H)7.02-7.12 (m, 2H) 7.16 (d, J=3.32 Hz, 1H) 7.20-7.26 (m, 2H) 7.33 (d,J=8.25 Hz, 1H) 7.74 (t, J=4.15 Hz, 1H) 7.81 (dd, J=8.27, 1.98 Hz, 1H)8.81 (d, J=1.90 Hz, 1H) 9.52 (s, 1H).

4-[3-[(5-Methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-butyricacid ethyl ester was prepared comprising the same procedure as compoundno. 11 from3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 533 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.19-1.29 (m, 3H) 1.93 (quin, J=7.05 Hz, 3H) 2.33-2.48 (m, 6H) 3.15 (dd,J=15.25, 5.64 Hz, 8H) 3.40-3.52 (m, 3H) 4.11 (q, J=7.13 Hz, 2H) 6.22 (d,J=2.64 Hz, 1H) 6.50 (t, J=5.08 Hz, 1H) 6.98-7.05 (m, 1H) 7.09-7.15 (m,2H) 7.16-7.25 (m, 2H) 7.33 (d, J=8.25 Hz, 1H) 7.60 (dd, J=8.25, 2.05 Hz,1H) 8.81 (s, 1H) 9.47 (brs, 1H).

Example 4 Synthetic route towards 5-methyl-furan-2-carboxylic acid[5-(3-amino-propylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

The preparation of following compounds was in line with Scheme 4:

{3-[3-[(5-Methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-propyl}-carbamicacid tert-butyl ester (compound no. 258) was prepared comprising ananalogous procedure used for compound no. 11 from the3-[(5-methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid.

LCMS (ESI) 576 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm0.81-0.90 (m, 1H) 1.08-1.17 (m, 1H) 1.23-1.31 (m, 1H) 1.43 (s, 9H)1.65-1.82 (m, 5H) 2.37 (s, 2H) 2.43 (s, 2H) 3.12-3.22 (m, 8H) 3.41 (s,2H) 6.09-6.25 (m, 1H) 6.97-7.06 (m, 1H) 7.13 (d, J=3.47 Hz, 2H)7.17-7.24 (m, 1H) 7.35 (s, 1H) 7.52-7.69 (m, 1H) 8.68-8.92 (m, 1H)9.38-9.59 (m, 1H).

5-Methyl-furan-2-carboxylicacid[5-(3-acetylaminopropylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 259) was prepared as follows:{3-[3-[(5-Methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-propyl}-carbamicacid tert-butyl ester, above, (0.20 g, 0.347 mmol) was stirred with amixture of CH₂Cl₂/TFA (5.0 mL/5.0 mL) for 3 h. The reaction wasconcentrated to give intermediate amine which was taken (0.070 g, 0.147mmol) in CH₂Cl₂ (2.0 mL). DIPEA (0.371 g, 2.87 mmol) was added to thisfollowed by acetic anhydride (0.32 g, 3.13 mmol). The reaction wasstirred at room temperature for 3 h, concentrated and the crude waspurified on preparative HPLC using water/methanol as eluent.

LCMS (ESI) 518 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.78 (quin,J=6.81 Hz, 2H) 1.93 (s, 3H) 2.34 (s, 3H) 2.43 (s, 3H) 3.12-3.21 (m, 8H)3.21-3.26 (m, 2H) 3.26-3.26 (m, 1H) 3.40 (t, J=6.88 Hz, 2H) 6.29 (dd,J=3.39, 0.85 Hz, 1H) 6.96-7.01 (m, 1H) 7.12-7.21 (m, 4H) 7.39 (d, J=8.30Hz, 1H) 7.61 (dd, J=8.30, 2.15 Hz, 1H) 8.69 (d, J=2.05 Hz, 1H).

5-Methyl-furan-2-carboxylic acid[5-[3-(3-ethyl-ureido)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amidewas prepared comprising an analogous procedure used for compound no. 48.

LCMS (ESI) 547 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.07 (t,J=7.22 Hz, 3H) 1.74 (t, J=6.69 Hz, 2H) 2.35 (s, 3H) 2.42 (s, 3H)3.08-3.23 (m, 12H) 3.41 (t, J=6.74 Hz, 2H) 6.28 (dd, J=3.32, 0.78 Hz,1H) 6.93-7.06 (m, 1H) 7.01 (s, 1H) 7.11-7.23 (m, 4H) 7.39 (d, J=8.35 Hz,1H) 7.61 (dd, J=8.30, 2.10 Hz, 1H) 8.69 (d, J=2.10 Hz, 1H).

{3-[3-[(5-Methyl-furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoylamino]-propyl}-carbamicacid methyl ester was prepared comprising an analogous procedure usedfor compound no. 133 from 5-methyl-furan-2-carboxylic acid[5-(3-amino-propylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide.

LCMS (ESI) 534 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.77 (t,J=6.76 Hz, 2H) 2.34 (s, 3H) 2.42 (s, 3H) 3.09-3.22 (m, 10H) 3.40 (t,J=6.86 Hz, 2H) 3.61 (s, 3H) 6.28 (d, J=3.32 Hz, 1H) 7.00 (dd, J=6.44,2.10 Hz, 1H) 7.11-7.23 (m, 4H) 7.38 (d, J=8.30 Hz, 1H) 7.60 (dd, J=8.27,2.07 Hz, 1H) 8.68 (d, J=2.00 Hz, 1H).

Example 5 Synthetic route towards thiophene-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-otolyl-piperazin-1-yl)-phenyl]-amide(compound no. 40)

Step 1

To a solution of 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.02 mmol) inCH₂Cl₂ (150 mL), HOBt (6.5 g, 48.63 mmol) and EDC.HCl (6.2 g, 40.53mmol) were added followed by DIPEA (6.12 mL, 35.12 mmol). The reactionwas stirred at room temperature for 6 h. Water (50.0 mL) was added andthe layers were separated. Organic layer was washed with brind andconcentrated to give crude product4-fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide (7.5 g,90%). This was taken to the next step without further purification.

Step 2

To a solution of4-Fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide (2.0 g,6.47 mmol) in DMF (10 mL), K₂CO₃ (1.7 g, 12.94 mmol) was added followedby 1-o-tolyl-piperazine (1.7 g, 9.7 mmol), and the reaction mixture wasstirred at room temperature for 16 h. DMF (2.0 mL) was added andfiltered. The solid was washed with MeOH (300 mL) and methanol layer wasevaporated to give the acid3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamidein the first crop (1.8 g, 62%).

Step 3

3-Nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide(1.5 g, 3.2 mmol) was taken in a mixture of ethanol/methanol (50.0mL/20.0 mL). This was added to a flask containing Pd/C (5 wt %) (0.15g). The solution was evacuated and nitrogen purged and stirred under aballoon of hydrogen for 8 h. LC-MS indicated completion of reaction.Reaction was stopped, evacuated and nitrogen purged and filtered oncelite. The solvent was rotavaped out to give3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide(0.7 g, 47%).

Step 4

In 20 mL scintillation vial, under nitrogen,3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide(0.06 g, 0.137 mmol) was dissolved in CH₂Cl₂ (2.0 mL), then DIPEA (0.12mL, 0.685 mmol) and DMAP (0.0016 g, 0.0137 mmol) were added and themixture was cooled to 0° C. Then the 2-thiophene chloride (0.206 mmol,0.03 g) in CH₂Cl₂ (1.0 mL) was added drop by drop. After 40 min thereaction was done. 10.0 mL of CH₂Cl₂ were added, and then it was washedwith 4.0 mL of water followed by 3.0 mL of a saturated sodiumbicarbonate solution and 3.0 mL of brine. Organics were dried overanhydrous sodium sulfate, filtered and concentrated. The crude wasdissolved in methanol and purified on preparative HPLC using MeOH/Water(0.1% TFA) to give the desired product (0.06 g, 81%).

LCMS (ESI) 546 (M+H); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.84 (quin,J=6.87 Hz, 2H) 2.04 (quin, J=7.60 Hz, 2H) 2.34 (s, 3H) 2.35-2.40 (m, 2H)3.18 (s, 7H) 3.33-3.40 (m, 4H) 3.44-3.53 (m, 2H) 6.97-7.04 (m, 1H)7.14-7.24 (m, 4H) 7.38 (d, J=8.40 Hz, 1H) 7.67 (dd, J=8.32, 2.12 Hz, 1H)7.75 (dd, J=4.98, 1.07 Hz, 1H) 7.86 (dd, J=3.73, 1.05 Hz, 1H) 8.48 (d,J=2.15 Hz, 1H).

The preparation of following compounds was in line with Scheme 5:

3-(2,2-Dimethyl-propionylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide(compound no. 177) was prepared comprising an analogous procedure usedfor compound no. 133 from3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide.

LCMS (ESI) 520 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 1.34(s, 9H) 1.83 (quin, J=6.32 Hz, 2H) 2.08 (quin, J=7.65 Hz, 2H) 2.38 (s,3H) 2.51 (t, J=8.13 Hz, 2H) 3.09-3.26 (m, 8H) 3.35-3.52 (m, 6H)7.03-7.09 (m, 1H) 7.12-7.17 (m, 1H) 7.19-7.25 (m, 2H) 7.36 (d, J=8.35Hz, 1H) 7.46-7.58 (m, 1H) 7.65 (dd, J=8.30, 2.15 Hz, 1H) 8.74 (d, J=2.10Hz, 1H) 8.91 (s, 1H).

3-(2-Cyclopropyl-acetylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide(compound no. 219) was prepared comprising an analogous procedure usedfor compound no. 133 from3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide.

LCMS (ESI) 518 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm0.04-0.05 (m, 2H) 0.38-0.47 (m, 2H) 0.51-0.59 (m, 1H) 0.79 (dddt,J=12.59, 7.56, 5.05, 2.51, 2.51 Hz, 1H) 0.94-1.00 (m, 1H) 1.44 (quin,J=6.15 Hz, 2H) 1.68-1.77 (m, 2H) 2.01-2.11 (m, 7H) 2.78 (s, 8H)3.01-3.12 (m, 6H) 6.66-6.73 (m, 1H) 6.76 (d, J=7.27 Hz, 1H) 6.84-6.91(m, 2H) 7.02 (d, J=8.30 Hz, 1H) 7.24-7.35 (m, 2H) 8.51 (d, J=1.61 Hz,1H) 8.62 (brs, 1H).

6-Methyl-pyridine-2-carboxylicacid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 186) was prepared comprising an analogous procedure usedfor compound no. 133 from3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide.

LCMS (ESI) 555 (M+H); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.76-1.91 (m,2H) 2.05 (quin, J=7.59 Hz, 2H) 2.33 (s, 3H) 2.35-2.41 (m, 2H) 2.68 (s,3H) 3.10-3.16 (m, 4H) 3.20-3.25 (m, 4H) 3.38 (td, J=6.91, 2.05 Hz, 4H)3.49 (t, J=7.08 Hz, 2H) 6.91-7.00 (m, 1H) 7.10-7.21 (m, 3H) 7.39 (d,J=8.35 Hz, 1H) 7.46 (d, J=7.76 Hz, 1H) 7.62 (dd, J=8.25, 2.10 Hz, 1H)7.88 (t, J=7.74 Hz, 1H) 8.04 (d, J=7.66 Hz, 1H) 8.93 (d, J=2.05 Hz, 1H).

N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-3-(pyrimidin-2-ylamino)-4-(4-o-tolyl-piperazin-1-yl)-benzamide(compound no. 242) was prepared as follows: In a microwavable glasstube, Pd(OAc)₂ (0.0025 g, 0.0115 mmol) and X-PHOS (5.4 mg, 0.0115 mmol)were taken in a mixture of t-BuOH:toluene (1:5) (2.0 mL) and stirred.This solution was evacuated for 5 min and purged with nitrogen.3-Amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide(0.05 g, 0.115 mmol) and 2-bromo-pyrimidine (2.7 mg, 0.172 mmol) wereadded to this, evacuated and nitrogen purged. This mixture was stirredat 140° C. under MW for 30 min. LC-MS indicated the product formationalong with some other by-products. The reaction mixture wasconcentrated, dissolved in methanol and purified on preparative HPLCusing water/methanol as eluent to give desire product (10.0 mg, 17%).

LCMS (ESI) 514 (M+H); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.15 (t,J=7.03 Hz, 1H) 1.84 (t, J=6.81 Hz, 2H) 1.96-2.10 (m, 2H) 2.27-2.34 (m,3H) 2.34-2.42 (m, 2H) 3.05-3.14 (m, 8H) 3.37 (q, J=6.74 Hz, 4H)3.43-3.54 (m, 3H) 6.80-6.99 (m, 2H) 7.04-7.19 (m, 3H) 7.33 (d, J=8.25Hz, 1H) 7.50 (dd, J=8.25, 2.10 Hz, 1H) 8.49 (d, J=4.83 Hz, 1H) 8.85 (d,J=2.10 Hz, 1H).

5-Bromo-furan-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 143) was prepared comprising an analogous procedure usedfor compound no. 133 from3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide.

LCMS (ESI) 608 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm 1.76(dt, J=11.99, 6.13 Hz, 4H) 1.95-2.12 (m, 2H) 2.26-2.46 (m, 5H) 2.98-3.25(m, 8H) 3.27-3.49 (m, 6H) 6.55 (d, J=3.56 Hz, 1H) 7.01 (dd, J=6.52, 2.27Hz, 1H) 7.12-7.26 (m, 3H) 7.33 (d, J=8.25 Hz, 1H) 7.67 (dd, J=8.18, 1.93Hz, 2H) 8.85 (d, J=1.90 Hz, 1H) 9.55 (s, 1H).

Example 6 Synthetic route towards 5-ethynyl-furan-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 176)

In a 20 mL scintillation vial, 5-bromo-furan-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(0.1 g, 0.231 mmol) was taken in acetonitrile (5.0 mL). Trimethylsilylacetylene (0.045 g, 0.462 mmol), CuI (0.009 g, 0.046 mmol),triethylamine (0.116 g, 1.155 mmol) and PdCl₂(Ph₃P) (0.032 g, 0.046mmol) were added to this, and the solution was evacuated for 5 min andnitrogen purged and stirred at 80° C. for 4 h. LC-MS indicated thecompletion of the reaction. It was diluted with acetonitrile andfiltered through celite and concentrated. The crude was dissolved in THFand stirred with TBAF (2.0 mL of 2 M solution in THF) at roomtemperature for 16 h. The reaction was concentrated and dissolved inmethanol and purified on preparative HPLC using methanol/water as eluentto give the desired product (0.018 g, 14% yield).

LCMS (ESI) 554 (M+H); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.28-1.37 (m,2H) 1.84 (quin, J=6.87 Hz, 2H) 2.04 (quin, J=7.59 Hz, 2H) 2.31-2.44 (m,5H) 3.11-3.21 (m, 4H) 3.36 (td, J=6.83, 3.17 Hz, 4H) 3.48 (t, J=7.05 Hz,2H) 4.18 (s, 1H) 6.88 (d, J=3.61 Hz, 1H) 6.99-7.08 (m, 1H) 7.17-7.31 (m,4H) 7.39 (d, J=8.30 Hz, 1H) 7.63 (dd, J=8.27, 2.07 Hz, 1H) 8.71 (d,J=2.00 Hz, 1H).

The preparation of following compound was in line with Scheme 6:

Furan-2,5-dicarboxylic acid 2-amide5-{[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide}(compound no. 216) was prepared as follows: 5-Bromo-furan-2-carboxylicacid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(0.1 g, 0.164 mmol), Zn(CN)₂ (0.038 g, 0.33 mmol), Zn (2.1 mg, 0.033mmol) were taken in DMA (5.0 mL) and the solution was degassed for 5min. Pd(t-Bu₃P)₂ (8.0 mg, 0.016 mmol) was added to this, and thesolution was degassed and nitrogen purged again. The reaction mixturewas stirred at 85° C. under nitrogen for 5 h. It was cooled, dissolvedin MeOH and purified on preparative HPLC using water/methanol as eluentto the intermediate nitrile (0.07 g, 79%). The above nitrile (0.05 g,0.09 mmol) was taken in DMSO (2.0 mL). K₂CO₃ (0.074 mg, 0.54 mmol) wasadded to this followed by H₂O₂ (0.031 g, 0.27 mmol) and the reaction wasstirred at room temperature for 4 h. LC-MS indicated the completion ofthe reaction. Water (2.0 mL) was added and the product crashed out. Itwas filtered and dried to give the desired product (0.025 g, 47%).

LCMS (ESI) 573 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.66 (quin, J=6.97Hz, 2H) 1.88 (quin, J=7.53 Hz, 2H) 2.15-2.21 (m, 2H) 2.25 (s, 3H) 3.04(s, 8H) 3.15-3.22 (m, 4H) 3.31 (t, J=6.98 Hz, 2H) 6.84-6.97 (m, 1H)7.07-7.16 (m, 3H) 7.23 (d, J=3.61 Hz, 1H) 7.29-7.34 (m, 2H) 7.64 (dd,J=8.42, 1.98 Hz, 2H) 8.09 (brs, 1H) 8.36 (t, J=5.64 Hz, 1H) 8.42 (d,J=2.00 Hz, 1H) 9.68 (s, 1H).

Example 7 Synthetic route towards furan-2-carboxylic acid{2-[4-(2-methyl-benzyl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide

Steps 1, 2, 3 and 4

Reactions were performed in a similar fashion as compound no. 11.

Step 5 and Step 6

To a solution of furan-2-carboxylic acid{5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-piperazin-1-yl-phenyl}-amide(0.1 g, 0.23 mmol) in acetonitrile (3.0 mL) and DMF (0.5 mL), K₂CO₃(0.094 g, 0.68 mmol) and 1-bromomethyl-2-methyl-benzene (0.05 g, 0.3mmol) were added and the reaction was stirred at room temperature for 4h. Water was added and extracted with DCM, concentrated and the crudewas purified on silica gel using DCM/MeOH (10%) to give the product(0.027 g, 22% yield).

LCMS (ESI) 544 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.85 (t,J=6.88 Hz, 2H) 2.00-2.11 (m, 2H) 2.38 (d, J=8.25 Hz, 2H) 2.42 (s, 3H)2.73 (brs, 4H) 2.98 (t, J=4.73 Hz, 4H) 3.34-3.41 (m, 4H) 3.50 (t, J=7.10Hz, 2H) 3.62 (s, 2H) 6.71 (dd, J=3.56, 1.76 Hz, 1H) 7.10-7.19 (m, 4H)7.26-7.31 (m, 2H) 7.32 (d, J=8.35 Hz, 1H) 7.61 (dd, J=8.32, 2.12 Hz, 1H)7.82 (dd, J=1.71, 0.68 Hz, 1H) 8.69 (d, J=2.10 Hz, 1H).

The preparation of following compounds was in line with Scheme 7:

4-{2-[(Furan-2-carbonyl)-amino]-4-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-piperazine-1-carboxylicacid ethyl ester (compound no. 62) was prepared comprising the sameprocedure as compound no. 11.

LCMS (ESI) 512 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.28 (t,J=7.10 Hz, 3H) 1.85 (t, J=6.91 Hz, 2H) 2.01-2.11 (m, 2H) 2.36-2.43 (m,2H) 2.91-2.99 (m, 4H) 3.34-3.41 (m, 4H) 3.50 (t, J=7.08 Hz, 2H) 3.71(brs, 4H) 4.16 (q, J=7.08 Hz, 2H) 6.68 (dd, J=3.54, 1.78 Hz, 1H) 7.29(dd, J=3.56, 0.68 Hz, 1H) 7.33 (d, J=8.35 Hz, 1H) 7.63 (dd, J=8.32, 2.12Hz, 1H) 7.81 (dd, J=1.73, 0.71 Hz, 1H) 8.69 (d, J=2.05 Hz, 1H).

5-Methyl-furan-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperidin-1-yl)-phenyl]-amide(compound no. 165) was prepared from the reaction between4-o-tolyl-piperidine and4-fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide,comprising the sequence of reactions described for the synthesis ofcompound no. 175.

LCMS (ESI) 543 (M+H); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.83 (quin,J=6.91 Hz, 2H) 1.88-1.95 (m, 2H) 1.99-2.09 (m, 4H) 2.13 (s, 1H)2.34-2.40 (m, 5H) 2.42 (s, 3H) 2.92-3.02 (m, 3H) 3.18 (d, J=11.18 Hz,2H) 3.32 (s, 1H) 3.36 (td, J=6.87, 3.88 Hz, 4H) 3.48 (t, J=7.08 Hz, 2H)6.28 (dd, J=3.37, 0.68 Hz, 1H) 7.01-7.20 (m, 4H) 7.34 (d, J=8.35 Hz, 2H)7.59 (dd, J=8.30, 2.10 Hz, 1H) 8.73 (d, J=2.05 Hz, 1H).

5-Methyl-furan-2-carboxylic acid{2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide(compound no. 130) was prepared from the reaction between1-(2-fluoro-phenyl)-piperazine and4-fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamidecomprising the sequence of reactions described for the synthesis ofcompound no. 175.

LCMS (ESI) 548 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ□ ppm 1.84 (t,J=6.91 Hz, 2H) 2.00-2.09 (m, 2H) 2.35 (s, 1H) 2.37-2.41 (m, 4H)3.11-3.16 (m, 4H) 3.30-3.40 (m, 8H) 3.48 (t, J=7.08 Hz, 2H) 6.28 (dd,J=3.39, 0.95 Hz, 1H) 6.94-7.09 (m, 2H) 7.09-7.12 (m, 2H) 7.15 (d, J=3.47Hz, 1H) 7.38 (d, J=8.30 Hz, 1H) 7.61 (dd, J=8.30, 2.10 Hz, 1H) 8.70 (d,J=2.10 Hz, 1H).

5-Methyl-furan-2-carboxylic acid{2-[4-(2-methoxy-phenyl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide(compound no. 173) was prepared from the reaction between1-(2-methoxy-phenyl)-piperazine and4-fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide,comprising the sequence of reactions described for the synthesis ofcompound no. 175.

LCMS (ESI) 560 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.76(t, J=6.03 Hz, 2H) 1.99-2.09 (m, 2H) 2.36-2.43 (m, 5H) 3.10-3.15 (m, 4H)3.25-3.44 (m, 10H) 3.87 (s, 3H) 6.20 (dd, J=3.37, 0.98 Hz, 1H) 6.89-7.05(m, 4H) 7.11 (d, J=3.32 Hz, 1H) 7.33 (d, J=8.25 Hz, 1H) 7.64 (dd,J=8.25, 2.10 Hz, 2H) 8.87 (d, J=2.10 Hz, 1H) 9.46 (s, 1H).

5-Methyl-furan-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-phenyl-piperazin-1-yl)-phenyl]-amide(compound no. 167) was prepared from the reaction between1-phenyl-piperazine and 1-(2-fluoro-phenyl)-piperazine and4-fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide,comprising the sequence of reactions described for the synthesis ofcompound no. 175.

LCMS (ESI) 530 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.89 (t,J=6.96 Hz, 2H) 2.05-2.14 (m, 2H) 2.39 (s, 3H) 2.40-2.45 (m, 2H)3.15-3.20 (m, 4H) 3.38-3.48 (m, 8H) 3.54 (t, J=7.08 Hz, 2H) 6.32 (dd,J=3.42, 0.98 Hz, 1H) 6.91 (t, J=7.35 Hz, 1H) 7.08 (d, J=7.91 Hz, 2H)7.20 (d, J=3.12 Hz, 1H) 7.27-7.33 (m, 2H) 7.41 (d, J=8.30 Hz, 1H) 7.66(dd, J=8.30, 2.10 Hz, 1H) 8.75 (d, J=2.05 Hz, 1H).

5-Methyl-furan-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-[1,4]diazepan-1-yl)-phenyl]-amide(compound no. 194) was prepared as follows: In a microwavable glasstube, Pd(OAc)₂ (33.6 mg, 0.15 mmol) and X-PHOS (71.4 mg, 0.15 mmol) weretaken in a mixture of t-BuOH:toluene (1:5) (4.0 mL) and stirred. Thissolution was evacuated for 5 min and purged with nitrogen.[1,4]Diazepane-1-carboxylic acid tert-butyl ester (0.2 g, 1.0 mmol) and1-bromo-2-methyl-benzene (0.255 mg, 1.5 mmol) were added to this,evacuated and nitrogen purged. This mixture was stirred at 140° C. underMW for 30 min. Reaction was cooled, concentrated on celite and purifiedon silica gel using CH₂Cl₂/MeOH (10%) to give the intermediate product,4-o-tolyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.15 g,51%). This was dissolved in CH₂Cl₂ (2.0 mL) and stirred withtrifluroacetic acid (1.0 mL) for 16 h. The reaction was concentrated andthe crude 1-o-tolyl-[1,4]diazepane was used in similar fashion describedfor compound no. 11.

LCMS (ESI) 558 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.67-1.81 (m, 3H) 1.96-2.17 (m, 4H) 2.30-2.41 (m, 8H) 3.22-3.44 (m, 13H)6.19 (d, J=2.64 Hz, 1H) 6.94 (s, 1H) 7.06-7.21 (m, 4H) 7.31 (d, J=8.30Hz, 1H) 7.51-7.65 (m, 2H) 8.87 (d, J=2.05 Hz, 1H) 9.55 (s, 1H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-[2-(1-methyl-1H-imidazol-4-yl)-ethylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amidewas prepared from 2-(1-methyl-1H-imidazol-4-yl)-ethyl amine and3-[(2-cyclopropyl-oxazole-4-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid obtained from the LiOH mediated hydrolysis of3-[(2-cyclopropyl-oxazole-4-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid methyl ester followed by HATU amide coupling using the desiredamine.

LCMS (ESI) 554 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.06-1.19 (m, 4H) 2.10 (s, 1H) 2.35 (s, 3H) 2.80 (t, J=6.22 Hz, 2H)3.06-3.20 (m, 8H) 3.59-3.69 (m, 5H) 6.75 (s, 1H) 7.01 (dd, J=7.27, 1.66Hz, 1H) 7.14-7.23 (m, 3H) 7.29 (d, J=8.25 Hz, 1H) 7.43 (s, 1H) 7.61 (dd,J=8.22, 2.12 Hz, 1H) 7.66-7.77 (m, 1H) 8.13 (s, 1H) 8.87 (d, J=2.05 Hz,1H) 9.94 (brs, 1H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-(4-acetylamino-butylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amidewas prepared from N-(4-amino-butyl)-acetamide and3-[(2-cyclopropyl-oxazole-4-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid obtained from the LiOH mediated hydrolysis of3-[(2-cyclopropyl-oxazole-4-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid methyl ester followed by HATU amide coupling using the desiredamine.

LCMS (ESI) 559 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.07-1.18 (m, 4H) 1.53-1.70 (m, 4H) 2.00 (s, 3H) 2.05-2.15 (m, 1H) 2.37(s, 3H) 3.09-3.24 (m, 8H) 3.30 (q, J=6.36 Hz, 2H) 3.43-3.51 (m, 2H)6.22-6.47 (m, 1H) 6.68 (brs, 1H) 6.97-7.35 (m, 5H) 7.61 (dd, J=8.22,2.07 Hz, 1H) 8.12 (s, 1H) 8.82 (d, J=2.05 Hz, 1H) 9.94 (s, 1H).

Example 8 Synthetic route towards 2-cyclopropyl-oxazole-4-carboxylicacid[5-[3-(2-methyl-5-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Step 1

To an ice-cold solution of NaH (0.505 g, 12.6 mmol) in DMF (20 mL)5-methyl-pyrrolidin-2-one (1.0 g, 10.1 mmol) in DMF (10.0 mL) was addedslowly. This was stirred for 30 min at 0-25° C.2-(3-Bromo-propyl)-isoindole-1,3-dione (2.47 g, 9.0 mmol) was added andthe reaction was stirred at room temperature for 16 h. A solution ofsaturated NH₄Cl (10.0 mL) was added and extracted with ethyl acetate.Organic layer was washed with LiCl solution and concentrated. The crudewas purified on silica gel using CH₂Cl₂/MeOH (10%) as eluent to give2-[3-(3-methyl-2-oxo-pyrrolidin-1-yl)-propyl]-isoindole-1,3-dione (1.2g, 41%).

Step 2

2-[3-(3-Methyl-2-oxo-pyrrolidin-1-yl)-propyl]-isoindole-1,3-dione (0.5g, 1.74 mmol) was taken in a mixture of THF/MeOH (3.0 mL/3.0 mL).Hydrazine hydrate (0.44 g, 8.7 mmol) was added to this and the reactionwas stirred at 50° C. for 16 h. The precipitate was filtered and thefiltrate was concentrated to give the product1-(3-amino-propyl)-5-methyl-pyrrolidin-2-one (0.12 g, 45%).

Step 3

1-(3-Amino-propyl)-5-methyl-pyrrolidin-2-one was coupled with3-[(2-cyclopropyl-oxazole-4-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoicacid,following HATU coupling procedure.

LCMS (ESI) 585 (M+H); ¹H NMR (400 MHz, DICHLOROMETHANE-d₂) δ ppm1.06-1.17 (m, 4H) 1.25 (d, J=6.30 Hz, 3H) 1.56-1.69 (m, 1H) 1.72-1.83(m, 2H) 2.09 (s, 1H) 2.18-2.30 (m, 1H) 2.39 (s, 3H) 2.42 (d, J=8.05 Hz,2H) 3.11-3.29 (m, 10H) 3.49-3.63 (m, 2H) 3.73 (d, J=6.78 Hz, 1H)7.01-7.10 (m, 1H) 7.16-7.27 (m, 3H) 7.31 (d, J=8.30 Hz, 1H) 7.64-7.78(m, 2H) 8.15 (s, 1H) 8.87 (d, J=2.00 Hz, 1H) 9.94 (brs, 1H).

General Scheme for HATU Coupling:

The preparation of following compounds was in line with Scheme 8:

Furan-2-carboxylic acidmethyl-[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide(compound no. 169) was prepared comprising the same procedure ascompound no. 258 from3-[(furan-2-carbonyl)-methyl-amino]-4-(4-o-tolyl-piperazin-1-yl) benzoicacid.

LCMS (ESI) 544 (M+H); ¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.84 (t,J=6.81 Hz, 2H) 2.08 (d, J=7.52 Hz, 2H) 2.41 (t, J=8.10 Hz, 2H) 2.79-2.98(m, 4H) 3.06-3.18 (m, 2H) 3.37 (q, J=7.08 Hz, 4H) 3.49 (t, J=7.08 Hz,4H) 6.03-6.18 (m, 1H) 6.24-6.34 (m, 1H) 6.94 (d, J=0.78 Hz, 1H) 7.04 (d,J=0.73 Hz, 1H) 7.15 (t, J=7.88 Hz, 3H) 7.42 (s, 1H) 7.77 (d, J=2.20 Hz,1H) 7.84 (dd, J=8.44, 2.20 Hz, 1H).

2-Cyclopropyl-oxazole-4-carboxylic acid[5-[2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amidewas prepared comprising the same procedure as compound no. 258 from3-[(furan-2-carbonyl)-methyl-amino]-4-(4-o-tolyl-piperazin-1-yl) benzoicacid.

LCMS (ESI) 540 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ□ ppm 1.06 (s, 2H) 1.14(s, 2H) 2.20 (s, 1H) 2.32 (s, 3H) 2.84 (s, 2H) 3.05 (brs, 4H) 3.08-3.21(m, 4H) 3.51 (s, 2H) 7.01 (s, 1H) 7.16 (s, 2H) 7.18-7.29 (m, 2H) 7.42(s, 1H) 7.56 (s, 1H) 8.29 (s, 1H) 8.54 (s, 1H) 8.67 (s, 1H) 8.79 (s, 1H)9.92 (s, 1H)

2-Methyl-thiazole-4-carboxylic acid[5-[2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amidewas prepared comprising the same procedure as compound no. 258 from3-[(furan-2-carbonyl)-methyl-amino]-4-(4-o-tolyl-piperazin-1-yl) benzoicacid.

LCMS (ESI) 530 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ□ ppm 2.31 (s, 3H) 2.77(s, 3H) 2.80-2.90 (m, 2H) 3.08 (brs, 4H) 3.11-3.23 (m, 4H) 3.47-3.61 (m,2H) 6.93-7.07 (m, 1H) 7.12 (s, 2H) 7.18-7.27 (m, 2H) 7.36-7.48 (m, 1H)7.53-7.64 (m, 1H) 8.15-8.24 (m, 1H) 8.33 (s, 1H) 8.47-8.60 (m, 1H) 8.84(d, J=2.00 Hz, 1H) 10.37-10.48 (m, 1H).

3-(Cyclopropanecarbonyl-amino)-N-[2-(3H-imidazol-4-yl)-ethyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamidewas prepared comprising the same procedure as compound no. 258 from3-[(furan-2-carbonyl)-methyl-amino]-4-(4-o-tolyl-piperazin-1-yl) benzoicacid.

LCMS (ESI) 473 (M+H); ¹H NMR (400 MHz, DMSO-d6) δ□ ppm 0.70-0.88 (m, 4H)1.96-2.12 (m, 1H) 2.30 (s, 3H) 2.69-2.80 (m, 2H) 3.07 (d, J=7.42 Hz, 8H)3.37-3.56 (m, 2H) 6.94-7.02 (m, 1H) 7.07-7.14 (m, 1H) 7.15-7.21 (m, 2H)7.21-7.27 (m, 1H) 7.49-7.56 (m, 1H) 7.55-7.64 (m, 1H) 8.20-8.32 (m, 1H)8.38-8.52 (m, 1H) 9.17-9.29 (m, 1H).

3-[(5-Methyl-furan-2-carbonyl)-amino]-4-(4-m-tolyl-piperazin-1-yl)-benzoicacid 3-(2-oxo-pyrrolidin-1-yl)-propyl ester (compound no. 243) wasprepared comprising the same procedure as the aniline intermediateaccording to compound no 40.

LCMS (ESI) 544 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.82 (s, 2H)2.08 (d, J=7.56 Hz, 2H) 2.36 (d, J=1.90 Hz, 6H) 2.45 (t, J=8.10 Hz, 2H)3.05-3.18 (m, 4H) 3.30-3.48 (m, 10H) 6.17 (dd, J=3.34, 0.95 Hz, 1H) 6.84(brs, 2H) 7.11-7.30 (m, 4H) 7.45-7.59 (m, 1H) 7.71 (d, J=2.10 Hz, 1H)8.96 (d, J=2.05 Hz, 1H) 9.38 (s, 1H).

3-[(5-Methyl-furan-2-carbonyl)-amino]-4-[4-(2-trifluoromethyl-phenyl)-piperazin-1-yl]-benzoicacid 3-(2-oxo-pyrrolidin-1-yl)-propyl ester (compound no. 246) wasprepared comprising the same procedure as the aniline intermediateaccording to compound no. 40.

LCMS (ESI) 598 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.82 (t,J=6.25 Hz, 2H) 1.98-2.15 (m, 2H) 2.35-2.52 (m, 5H) 3.04-3.14 (m, 4H)3.15-3.25 (m, 4H) 3.28-3.51 (m, 6H) 6.21 (dd, J=3.37, 0.88 Hz, 1H) 7.17(d, J=3.37 Hz, 1H) 7.28-7.34 (m, 2H) 7.44 (d, J=7.96 Hz, 2H) 7.58 (s,1H) 7.64-7.78 (m, 2H) 8.96 (d, J=2.05 Hz, 1H) 9.46 (s, 1H) ¹⁹F NMR (376MHz, CHLOROFORM-d) δ ppm −60.77 (s, 3 F).

4-[4-(2,6-Dimethyl-phenyl)-piperazin-1-yl]-3-[(5-methyl-furan-2-carbonyl)-amino]-benzoicacid 3-(2-oxo-pyrrolidin-1-yl)-propyl ester was prepared comprising thesame procedure as the aniline intermediate according to compound no. 40.

LCMS (ESI) 558 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.81-1.88 (m,2H) 2.07 (quin, J=7.58 Hz, 2H) 2.33-2.51 (m, 12H) 3.05 (t, J=4.54 Hz,4H) 3.36 (brs, 4H) 3.40-3.53 (m, 6H) 6.20 (dd, J=3.37, 0.93 Hz, 1H)6.94-7.09 (m, 2H) 7.18 (d, J=3.37 Hz, 1H) 7.31 (d, J=8.30 Hz, 1H) 7.53(t, J=6.10 Hz, 1H) 7.73 (dd, J=8.25, 2.10 Hz, 1H) 8.99 (d, J=2.05 Hz,1H) 9.48 (s, 1H).

3-[(2-Cyclopropyl-oxazole-4-carbonyl)-amino]-4-(4-m-tolyl-piperazin-1-yl)-benzoicacid 3-(2-oxo-pyrrolidin-1-yl)-propyl ester (compound no. 249) wasprepared comprising the same procedure as the aniline intermediateaccording to compound no. 40 (HATU coupling of2-cyclopropyl-1,3-oxazole-4-carboxylic acid replacing the acidchloride).

LCMS (ESI) 571 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.14 (m,4H) 1.81 (quin, J=6.21 Hz, 2H) 1.95-2.15 (m, 3H) 2.36 (s, 3H) 2.45 (t,J=8.10 Hz, 2H) 2.96-3.20 (m, 4H) 3.27-3.53 (m, 10H) 6.75 (d, J=7.32 Hz,1H) 6.80-6.92 (m, 2H) 7.11-7.26 (m, 2H) 7.61 (t, J=6.05 Hz, 1H) 7.73(dd, J=8.25, 2.00 Hz, 1H) 8.13 (s, 1H) 8.97 (d, J=1.95 Hz, 1H) 9.88 (s,1H).

3-[(2-Cyclopropyl-oxazole-4-carbonyl)-amino]-4-[4-(2-trifluoromethyl-phenyl)-piperazin-1-yl]-benzoicacid-3-(2-oxo-pyrrolidin-1-yl)-propyl ester (compound no. 250) wasprepared comprising the same procedure as the aniline intermediateaccording to compound no. 40 (HATU coupling of2-cyclopropyl-1,3-oxazole-4-carboxylic acid replacing the acidchloride).

LCMS (ESI) 625 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.29 (m,4H) 1.82 (s, 2H) 2.07 (s, 3H) 2.38-2.52 (m, 2H) 3.02-3.12 (m, 4H) 3.21(d, J=3.95 Hz, 4H) 3.43 (t, J=6.20 Hz, 6H) 7.29 (d, J=8.35 Hz, 2H) 7.54(s, 3H) 7.64-7.78 (m, 2H) 8.15 (s, 1H) 8.99 (d, J=2.00 Hz, 1H) 9.85-9.97(m, 1H) ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ ppm −60.76 (s, 3 F).

3-[(2-Cyclopropyl-oxazole-4-carbonyl)-amino]-4-[4-(2,6-dimethyl-phenyl)-piperazin-1-yl]-benzoicacid 3-(2-oxo-pyrrolidin-1-yl)-propyl ester was prepared comprising thesame procedure as the aniline intermediate according to compound no. 40(HATU coupling of 2-cyclopropyl-1,3-oxazole-4-carboxylic acid replacingthe acid chloride).

LCMS (ESI) 585 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.24 (m,4H) 1.74-1.88 (m, 2H) 2.07 (s, 3H) 2.31-2.52 (m, 8H) 3.04 (t, J=4.54 Hz,4H) 3.29-3.51 (m, 10H) 6.93-7.10 (m, 3H) 7.30 (s, 1H) 7.48-7.59 (m, 1H)7.68-7.80 (m, 1H) 8.14 (s, 1H) 9.01 (d, J=2.10 Hz, 1H) 9.82-9.94 (m,1H).

3-[(2-Cyclopropyl-oxazole-4-carbonyl)-amino]-4-[4-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-benzoicacid-3-(2-oxo-pyrrolidin-1-yl)-propyl ester was prepared comprising thesame procedure as the aniline intermediate according to compound no. 40(HATU coupling of 2-cyclopropyl-1,3-oxazole-4-carboxylic acid replacingthe acid chloride).

LCMS (ESI) 589 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.23 (m,4H) 1.81 (quin, J=6.22 Hz, 2H) 1.96-2.17 (m, 3H) 2.36 (s, 3H) 2.40-2.49(m, 2H) 2.95-3.20 (m, 8H) 3.31-3.49 (m, 6H) 6.80-6.99 (m, 2H) 7.12 (dd,J=8.71, 5.30 Hz, 1H) 7.28 (s, 1H) 7.64 (t, J=6.05 Hz, 1H) 7.73 (dd,J=8.27, 2.07 Hz, 1H) 8.13 (s, 1H) 8.97 (d, J=2.05 Hz, 1H) 9.94 (s, 1H)¹⁹F NMR (376 MHz, CHLOROFORM-d) δ ppm −120.69 (td, J=8.74, 5.28 Hz, 1F).

4-[4-(2-Bromo-phenyl)-piperazin-1-yl]-3-[(2-cyclopropyl-oxazole-4-carbonyl)-amino]-benzoicacid 3-(2-oxo-pyrrolidin-1-yl)-propyl ester was prepared comprising thesame procedure as the aniline intermediate according to compound no. 40(HATU coupling of 2-cyclopropyl-1,3-oxazole-4-carboxylic acid replacingthe acid chloride).

LCMS (ESI) 635 (M+H); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.23 (m,4H) 1.81 (quin, J=6.22 Hz, 2H) 1.92-2.15 (m, 3H) 2.45 (t, J=8.10 Hz, 2H)3.14 (t, J=4.42 Hz, 4H) 3.32 (brs, 4H) 3.38-3.47 (m, 6H) 6.97 (td,J=7.61, 1.46 Hz, 1H) 7.19 (dd, J=8.00, 1.32 Hz, 1H) 7.28-7.38 (m, 2H)7.55-7.65 (m, 2H) 7.74 (dd, J=8.27, 2.07 Hz, 1H) 8.13 (s, 1H) 8.97 (d,J=1.95 Hz, 1H) 9.95 (s, 1H).

3-[(5-Methyl-furan-2-carbonyl)-amino]-4-[4-(2-nitro-phenyl)-piperazin-1-yl]-benzoicacid 3-(2-oxo-pyrrolidin-1-yl)-propyl ester was prepared comprising thesame procedure from the piperazine intermediate according tofuran-2-carboxylic acid{2-[4-(2-methyl-benzyl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide.

LCMS (ESI) 575 (M+H) ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.81 (quin,J=6.25 Hz, 2H) 2.03-2.13 (m, 3H) 2.29-2.49 (m, 5H) 3.05-3.17 (m, 4H)3.25-3.36 (m, 4H) 3.37-3.49 (m, 5H) 6.11-6.25 (m, 1H) 7.05-7.28 (m, 4H)7.46-7.60 (m, 2H) 7.71 (dd, J=8.25, 2.00 Hz, 1H) 7.81 (dd, J=8.13, 1.29Hz, 1H) 8.95 (d, J=1.95 Hz, 1H) 9.39 (s, 1H).

Example 9 Synthetic route towards thiophene-3-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

To a suspension of3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide(0.1 g, 0.229 mmol) in methylene dichloride (5 ml), triethylamine (0.069g, 0.489 mmol), thiophene-3-carboxylic acid (0.044 g, 0.344 mmol) and1-propane phosphonic cyclic anhydride (0.21 g, 0.489 mmol) were added.The reaction mixture was stirred for 16 h at room temperature. Thereaction mixture was concentrated and extracted with dichloromethane (10ml×1). The organic layer was washed with water (10 ml×2) and dried overanhydrous sodium sulphate. The organic layer was concentrated and thecrude product obtained was purified by flash chromatography using silicagel column to get (0.34 g, 34%) of the titled compound as a brown solid.

LCMS: Mass found (M+546.3).

Method: A—0.1% TFA in water, B—0.1% TFA in ACN: Flow—2 ml/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode.

Rt (min): 4.17 Area %:—97.91 (Max), 98.87 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.4 (s, 1H), 8.9 (s, 1H), 8.10 (s, 1H), 7.77(dd, J=1.52, 6.68 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=4.2 Hz, 1H), 7.44(dd, J=3.0, 8.04 Hz, 1H), 7.37 (d, J=8.28 Hz, 1H), 7.25 (t, J=5.36 Hz,2H), 7.22-7.13 (m, 1H), 7.07-7.03 (m, 1H), 3.45-3.40 (m, 6H), 3.16 (m,8H), 2.47 ((t, J=7.92 Hz, 2H), 2.36 (s, 3H), 2.11-2.03 (m, 2H), 1.83 (t,J=6.08 Hz, 2H).

The following compounds were prepared in a similar manner unlessdescribed otherwise. LCMS and HPLC analysis were performed as follows:Method: A—0.1% TFA in water, B—0.1% TFA in ACN: Flow—2 ml/min; Column:XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode.

2-Bromo-thiazole-5-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 25.1%.

Color and appearance: White solid.

LCMS: Mass found (M+625.0).

Rt (min): 4.26 Area %:—95.75 (Max), 95.35 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.38 (s, 1H), 8.83 (s, 1H), 8.17 (s, 1H), 7.81(d, J=8.08 Hz, 1H) 7.74 (s, 1H), 7.41 (d, J=8.36 Hz, 1H), 7.24 (d,J=7.32 Hz, 2H), 7.16 (d, J=7.68 Hz, 1H), 7.09 (t, J=7.28 Hz, 1H),3.45-3.40 (m, 6H), 3.21 (m, 8H), 2.49 (t, J=7.88 Hz, 2H), 2.38 (s, 3H),2.10 (t, J=7.64 Hz, 2H), 1.82 (t, J=5.4 Hz, 2H).

3-(3-Methyl-butyrylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 23.4%.

Color and appearance: White solid.

LCMS: Mass found (M+520.3).

Rt (min): 4.26 Area %:—97.85 (Max), 98.03 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 2H), 7.74 (d, J=8.16 Hz, 1H), 7.58(s, 1H), 7.34 (d, J=8.16 Hz, 1H) 7.25 (t, J=7.32 Hz, 2H), 7.16 (d,J=7.84 Hz, 1H), 7.09 (t, J=7.64 Hz, 1H), 3.44-3.38 (m, 6H), 3.21 (m,8H), 2.46 (t, J=7.92 Hz, 2H), 2.38 (s, 3H), 2.35 (t, J=6.8 Hz, 2H),2.28-2.25 (m, 1H), 2.11-2.02 (m, 2H), 1.83-1.79 (m, 2H), 1.11 (d, 6H).

3-Benzoylamino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 53.4%.

Color and appearance: White solid.

LCMS: Mass found (M+540.3).

Rt (min): 4.35 Area %:—95.75 (Max), 98.12 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.38 (s, 1H), 9.04 (s, 1H), 7.98 (dd, J=1.12,7.84 Hz, 2H), 7.76 (dd, J=2.04, 8.24 Hz, 1H) 7.58-7.51 (m, 4H), 7.36 (d,J=8.28 Hz, 1H), 7.24 (t, J=7.44 Hz, 2H), 7.09-7.02 (m, 2H), 3.45-3.41(m, 6H), 3.12 (m, 8H), 2.47 (t, J=7.92 Hz, 2H), 2.36 (s, 3H), 2.09 (m,2H), 1.84 (t, J=6.24 Hz, 2H).

3-(3-Chloro-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 34.1%.

Color and appearance: White solid.

LCMS: Mass found (M+574.3).

Rt (min): 4.72 Area %:—96.54 (Max), 97.81 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.46 (s, 1H), 9.00 (s, 1H), 8.00 (s, 1H), 7.86(d, J=7.52 Hz, 1H) 7.77 (d, J=8.12 Hz, 1H), 7.61 (m, 1H), 7.56 (d,J=7.88 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.38 (d, J=8.24 Hz, 1H), 7.24(t, J=7.0 Hz, 2H), 7.13 (d, J=8.12 Hz, 1H), 7.07 (t, J=7.36 Hz, 1H),3.45-3.43 (m, 6H), 3.15 (m, 8H), 2.48-2.44 (m, 2H), 2.37 (s, 3H),2.12-2.04 (m, 2H), 1.85-1.79 (m, 2H).

3-(4-Chloro-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 44.7%.

Color and appearance: White solid.

LCMS: Mass found (M+574.3).

Rt (min): 4.75 Area %:—98.33 (Max), 98.98 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.61 (s, 1H), 8.90 (s, 1H), 7.98 (d, J=7.04Hz, 2H), 7.81 (d, J=7.72 Hz, 1H) 7.73 (s, 1H), 7.52 (d, J=8.28 Hz, 2H),7.41 (d, J=8.16 Hz, 1H), 7.23 (d, J=5.16 Hz, 2H), 7.13 (d, J=8.12 Hz,1H), 7.08 (t, J=7.32 Hz, 1H), 3.45-3.41 (m, 6H), 3.22 (m, 8H), 2.48 (t,J=8.00 Hz, 2H), 2.37 (s, 3H), 2.12-2.04 (m, 2H), 1.85-1.79 (m, 2H).

3-(3-Fluoro-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 23.5%.

Color and appearance: Brown solid.

LCMS: Mass found (M+558.3).

Rt (min): 4.46 Area %:—95.23 (Max), 97.78 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.5 (s, 1H), 8.97 (s, 1H), 7.79-7.68 (m, 4H),7.54-7.48 (m, 1H) 7.39 (d, J=8.28 Hz, 1H), 7.30 (d, J=1.84 Hz, 1H), 7.25(t, J=4.36 Hz, 2H), 7.13 (d, J=7.84 Hz, 1H), 7.08 (t, J=7.48 Hz, 1H),3.46-3.41 (m, 6H), 3.17 (m, 8H), 2.48 (t, J=7.92 Hz, 2H), 2.37 (s, 3H),2.12-2.05 (m, 2H), 1.84 (t, J=6.2 Hz, 2H).

3-(4-Fluoro-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 39.1%.

Color and appearance: White solid.

LCMS: Mass found (M+558.3).

Rt (min): 4.45 Area %:—94.80 (Max), 96.67 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 9.01 (d, J=2.0 Hz, 1H),7.99-7.96 (m, 2H), 7.76 (dd, J=2.08, 8.28 Hz, 1H) 7.63 (t, J=6.04 Hz,1H), 7.36 (d, J=8.28 Hz, 1H), 7.23-7.21 (m, 4H), 7.09-7.03 (m, 2H),3.45-3.41 (m, 6H), 3.3.11 (m, 8H), 2.48 (t, J=7.92 Hz, 2H), 2.36 (s,3H), 2.11-2.06 (m, 2H), 1.85-1.80 (m, 2H).

3-(3-Cyano-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 23.8%.

Color and appearance: Brown solid.

LCMS: Mass found (M+565.3).

Rt (min): 4.16 Area %:—97.43 (Max), 98.93 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.49 (s, 1H), 8.97 (s, 1H), 8.32 (s, 1H), 8.21(s, 1H) 7.87 (d, J=7.68 Hz, 1H), 7.81 (s, 1H), 7.69 (t, J=7.8 Hz, 1H),7.41 (d, J=8.32 Hz, 1H), 7.26-7.21 (m, 3H), 7.14 (d, J=8.00 Hz, 1H),7.07 (t, J=7.24 Hz, 1H), 3.46-3.42 (m, 6H), 3.17 (m, 8H), 2.49 (t,J=7.92 Hz, 2H), 2.36 (s, 3H), 2.13-2.07 (m, 2H), 1.83 (t, J=5.68 Hz,2H).

3-(4-Cyano-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 39.2%.

Color and appearance: White solid.

LCMS: Mass found (M+565.3).

Rt (min): 4.20 Area %:—96.63 (Max), 96.91 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.61 (s, 1H), 8.95 (s, 1H), 8.12 (d, J=6.8 Hz,2H), 7.85-7.81 (m, 4H) 7.42 (d, J=8.2 Hz, 1H), 7.25 (d, J=5.04 Hz, 2H),7.10 (m, 2H), 3.46-3.41 (m, 6H), 3.18 (m, 8H), 2.49 (t, J=7.96 Hz, 2H),2.36 (s, 3H), 2.11-2.07 (m, 2H), 1.83 (t, J=5.36 Hz, 2H).

3-(3-Methyl-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 53.7%.

Color and appearance: White solid.

LCMS: Mass found (M+554.3).

Rt (min): 4.66 Area %:—95.87 (Max), 97.22 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.40 (s, 1H), 9.03 (s, 1H), 7.82 (s, 1H), 7.75(d, J=6.6 Hz, 2H) 7.58 (t, J=5.8 Hz, 1H), 7.43-7.34 (m, 3H), 7.24 (t,J=7.36 Hz, 2H), 7.09-7.02 (m, 2H), 3.45-3.42 (m, 6H), 3.12 (m, 8H),2.47-2.41 (m, 5H), 2.2.36 (s, 3H), 2.11-2.03 (m, 2H), 1.86-1.80 (m, 2H).

3-(4-Methyl-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 39.5%.

Color and appearance: Brown solid.

LCMS: Mass found (M+554.3).

Rt (min): 4.67 Area %:—97.74 (Max), 98.64 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.38 (s, 1H), 8.99 (s, 1H), 7.89 (d, J=8.08Hz, 2H), 7.76 (dd, J=1.92, 8.24 Hz, 1H) 7.55 (s, 1H), 7.36 (t, J=8.4 Hz,3H), 7.24-7.21 (m, 2H), 7.11 (d, J=4.84 Hz, 1H), 7.09 (t, J=11.2 Hz,1H), 3.45-3.41 (m, 6H), 3.15 (m, 8H), 2.47-2.43 (m, 5H), 2.36 (s, 3H),2.11-2.03 (m, 2H), 1.85-1.79 (m, 2H).

Pyridine-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 69.4%.

Color and appearance: Brown solid.

LCMS: Mass found (M+541.3).

Rt (min): 4.23 Area %:—96.20 (Max), 96.53 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 11.07 (s, 1H), 9.06 (s, 1H), 8.66 (d, J=4.4Hz, 1H), 8.35 (d, J=4.4 Hz, 1H), 7.14 (d, J=7.76 Hz, 1H), 7.94 (d,J=6.32 Hz, 1H), 7.77 (dd, J=1.92, 6.36 Hz, 1H), 7.61 (t, J=5.6 Hz, 1H),7.50 (t, J=4.76 Hz, 1H), 7.31-7.24 (m, 3H), 7.09 (t, J=7.12 Hz, 1H),3.46-3.43 (m, 6H), 3.28-3.21 (m, 8H), 2.48-2.41 (m, 5H), 2.09-2.04 (m,2H), 1.86-1.80 (m, 2H).

N-[5-[3-(2-Oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-nicotinamide

Yield: 42.0%.

Color and appearance: White solid.

LCMS: Mass found (M+541.3).

Rt (min): 3.12 Area %:—96.61 (Max), 96.94 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.52 (s, 1H), 9.21 (s, 1H), 9.00 (s, 1H), 8.81(d, J=3.68 Hz, 1H), 8.40 (d, J=6.88 Hz, 1H), 7.81-7.75 (m, 2H),7.80-7.75 (m, 1H), 7.55 (d, J=4.68 Hz, 1H), 7.23-7.20 (m, 2H), 7.13 (d,J=7.76 Hz, 1H), 7.06 (t, J=7.92 Hz, 1H), 3.46-3.41 (m, 6H), 3.16 (m,8H), 2.49 (t, J=7.92 Hz, 2H), 2.36 (s, 3H), 2.10 (t, J=7.52 Hz, 2H),1.83 (t, J=5.72 Hz, 2H).

N-[5-[3-(2-Oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-isonicotinamide

Yield: 45.7%.

Color and appearance: White solid.

LCMS: Mass found (M+541.3).

Rt (min): 3.02 Area %:—97.96 (Max), 98.48 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.48 (s, 1H), 9.04 (s, 1H), 8.86 (d, J=5.96Hz, 2H), 7.81-7.77 (m, 3H) 7.74 (t, J=6.08 Hz, 1H), 7.39 (d, J=8.32 Hz,1H), 7.25-7.21 (m, 2H), 7.10-7.05 (m, 2H), 3.46-3.41 (m, 6H), 3.12 (m,8H), 2.49 (t, J=7.96 Hz, 2H), 2.36 (s, 3H), 2.12-2.07 (m, 2H), 1.83 (t,J=6.04 Hz, 2H).

N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-3-(3-trifluoromethyl-benzoylamino)-benzamide

Yield: 32.7%.

Color and appearance: White solid.

LCMS: Mass found (M+608.3).

Rt (min): 4.98 Area %:—98.14 (Max), 99.10 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.66 (s, 1H), 9.01 (s, 1H), 8.27-8.22 (m, 2H),7.85-7.67 (m, 4H) 7.41 (d, J=8.24 Hz, 1H), 7.23 (d, J=7.16 Hz, 2H), 7.12(d, J=8.0 Hz, 1H), 7.08 (d, J=7.28 Hz, 1H), 3.46-3.43 (m, 6H), 317 (m,8H), 2.49 (t, J=8.0 Hz, 2H), 2.37 (s, 3H), 2.10 (t, J=7.48 Hz, 2H), 1.84(t, J=6.08 Hz, 2H).

N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-3-(4-trifluoromethyl-benzoylamino)-benzamide

Yield: 60.5%.

Color and appearance: White solid.

LCMS: Mass found (M+608.3).

Rt (min): 5.00 Area %:—99.07 (Max), 98.92 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.53 (s, 1H), 8.99 (s, 1H), 8.12 (d, J=7.92Hz, 2H), 7.81-7.78 (m, 3H) 7.72 (s, 1H), 7.41 (d, J=8.28 Hz, 1H),7.25-7.22 (m, 2H), 7.11-7.03 (m, 2H), 3.46-3.41 (m, 6H), 3.17 (m, 8H),2.48 (t, J=7.92 Hz, 2H), 2.36 (s, 3H), 2.12-2.06 (m, 2H), 1.85-1.79 (m,2H).

3-(2-Methoxy-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 60.5%.

Color and appearance: White solid.

LCMS: Mass found (M+570.3).

Rt (min): 4.54 Area %:—97.66 (Max), 98.26 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 10.46 (s, 1H), 8.86 (s, 1H), 8.34 (dd, J=1.64,7.84 Hz, 1H), 7.75 (dd, J=2.0, 8.28 Hz, 1H) 7.54 (m, 1H), 7.44 (t,J=5.48 Hz, 1H), 7.30-7.28 (m, 3H), 7.24-7.17 (m, 1H), 7.10-7.05 (m, 3H),4.13 (s, 3H), 3.45-3.41 (m, 6H), 3.20-3.18 (m, 8H), 2.46-2.42 (t, J=7.96Hz, 2H), 2.40 (s, 3H), 2.09 (t, J=7.56 Hz, 2H), 1.84 (t, J=6.2 Hz, 2H).

3-(4-Methoxy-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 21.1%.

Color and appearance: White solid.

LCMS: Mass found (M+570.3).

Rt (min): 4.36 Area %:—94.07 (Max), 94.05 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.45 (s, 1H), 8.94 (s, 1H), 7.99 (d, J=7.8 Hz,2H), 7.77 (d, J=7.96 Hz, 1H) 7.56 (s, 1H), 7.38 (d, J=8.32 Hz, 1H),7.24-7.21 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 7.08-7.00 (m, 3H), 3.89 (s,3H), 3.45-3.42 (m, 6H), 3.20 (m, 8H), 2.47 (d, J=8.04 Hz, 2H), 2.37 (s,3H), 2.11-2.04 (m, 2H), 1.85-1.79 (m, 2H).

Naphthalene-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 16.2%.

Color and appearance: White solid.

LCMS: Mass found (M+590.3).

Rt (min): 4.86 Area %:—98.40 (Max), 97.81 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.61 (s, 1H), 9.07 (s, 1H), 8.54 (s, 1H),8.04-7.92 (m, 4H) 7.79 (d, J=8.12 Hz, 1H), 7.67-7.57 (m, 3H), 7.39 (d,J=8.32 Hz, 1H), 7.22 (t, J=6.68 Hz, 2H), 7.11-7.07 (m, 2H), 3.45-3.43(m, 6H), 3.18 (m, 8H), 2.48 ((t, J=7.92 Hz, 2H), 2.37 (s, 3H), 2.10 (t,J=7.48 Hz, 2H), 1.85 (t, J=5.92 Hz, 2H).

Quinoline-8-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 50.4%.

Color and appearance: Brown solid.

LCMS: Mass found (M+591.3).

Rt (min): 4.33 Area %:—95.24 (Max), 97.34 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 13.54 (s, 1H), 9.20 (dd, J=1.8, 4.28 Hz, 1H),9.03 (dd, J=1.52, 7.4 Hz, 1H), 8.98 (s, 1H) 8.36 (dd, J=1.76, 8.28 Hz,1H), 8.06 (dd, J=1.48, 8.12 Hz, 1H), 7.78-7.77 (m, 2H), 7.76-7.75 (m,1H), 7.58-7.55 (m, 1H), 7.31 (m, 1H), 7.29 (m, 2H), 7.19 (m, 2H),3.46-3.42 (m, 6H), 3.23-3.14 (m, 8H), 2.46-2.42 (t, J=7.92 Hz, 2H), 2.35(s, 3H), 2.09-2.07 (m, 2H), 1.84 (m, 2H).

4-Methyl-thiazole-5-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 78%.

Color and appearance: Brown solid.

LCMS: Mass found (M+561.3).

Rt (min): 3.80 Area %:—92.03 (Max), 95.82 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 7.76(dd, J=2.04, 8.32 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J=8.28 Hz, 1H), 7.25(t, J=7.52 Hz, 2H), 7.13 (d, J=7.72 Hz, 1H), 7.08 (t, J=7.96 Hz, 1H),3.46-3.40 (m, 6H), 3.17-3.15 (m, 8H), 2.89 (s, 3H), 2.47 (t, J=7.96 Hz,2H), 2.39 (s, 3H), 2.12-2.04 (m, 2H), 1.85-1.79 (m, 2H).

2-Methyl-4-trifluoromethyl-thiazole-5-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 11.7%.

Color and appearance: White solid.

LCMS: Mass found (M+629.3).

Rt (min): 4.30 Area %:—95.39 (Max), 98.27 (254 nm).

¹H NMR (400 MHz, CDCL₃) δ 9.28 (s, 1H), 8.83 (s, 1H), 7.79 (dd, J=1.76,8.32 Hz, 1H), 7.6 (s, 1H), 7.41 (d, J=8.28 Hz, 1H), 7.22 (d, J=7.6 Hz,2H), 7.07-7.01 (m, 2H), 3.45.3.40 (m, 6H), 3.06 (m, 8H), 2.79 (s 3H),2.47 (t, J=8.0 Hz, 2H), 2.36 (s, 3H), 2.12-2.04 (m, 2H), 1.83-1.80 (m,2H).

2-Bromo-4-methyl-thiazole-5-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 15.2%.

Color and appearance: White solid.

LCMS: Mass found (M+639.0).

Rt (min): 4.54 Area %:—94.07 (Max), 94.89 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.90 (s, 1H), 7.77 (dd, J=1.96,8.28 Hz, 1H), 7.63 (t, J=5.52 Hz, 1H), 7.40 (d, J=8.32 Hz, 1H), 7.25 (t,J=5.96 Hz, 2H), 7.12 (d, J=7.76 Hz, 1H), 7.08-7.04 (m, 1H), 3.45-3.40(m, 6H), 3.14-3.12 (m, 8H), 2.83 (s, 3H), 2.47 ((t, J=7.92 Hz, 2H), 2.37(s, 3H), 2.12-2.04 (m, 2H), 1.84-1.78 (m, 2H).

Thiazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 40.7%.

Color and appearance: Brown gum.

LCMS: Mass found (M+547.2).

Rt (min): 3.98 Area %:—96.25 (Max), 96.95 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H), 9.03 (s, 1H), 8.84 (s, 1H),9.32 (d, J=2.04 Hz, 1H), 7.77-7.49 (m, 1H), 7.62 (s, 1H), 7.32 (d,J=8.28 Hz, 1H), 7.24 (m, 3H), 7.08 (s, 1H), 3.45-3.42 (m, 6H), 3.29-3.21(m, 8H), 2.48-2.43 (m, 5H), 2.11-2.04 (m, 2H), 1.85-1.79 (m, 2H).

2-Methyl-thiazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 35.4%.

Color and appearance: Brown solid.

LCMS: Mass found (M+561.3).

Rt (min): 4.32 Area %:—96.08 (Max), 98.00 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 10.36 (s, 1H), 9.02 (s, 1H), 8.09 (s, 1H),7.751 (dd, J=2.04, 8.24 Hz, 1H), 7.55 (t, J=11.72 Hz, 1H), 7.34-7.22 (m,4H), 7.17 (t, J=7.88 Hz, 1H), 3.45-3.33 (m, 14H), 2.80 (s, 3H), 2.53 (s,3H), 2.48 (t, J=7.96 Hz, 2H), 2.11-2.05 (m, 2H), 1.83-1.79 (m, 2H).

2-Methyl-oxazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 54.7%.

Color and appearance: Brown gum.

LCMS: Mass found (M+545.3).

Rt (min): 4.02 Area %:—96.73 (Max), 97.79 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.91 (s, 1H), 8.99 (s, 1H), 8.19 (s, 1H), 7.75(dd, J=2.04, 8.32 Hz, 1H), 7.60 (t, J=6.0 Hz, 1H), 7.31 (d, J=8.28 Hz,1H), 7.24 (t, J=5.56 Hz, 3H), 7.06 (t, J=4.72 Hz, 1H), 3.45-3.40 (m,6H), 3.26-3.17 (m, 8H), 2.52 (s, 3H), 2.48 (t, J=7.96 Hz, 2H), 2.42 (s,3H), 2.11-2.03 (m, 2H), 1.84-1.78 (m, 2H).

2-Methyl-5-trifluoromethyl-oxazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 63.0%.

Color and appearance: White solid.

LCMS: Mass found (M+613.3).

Rt (min): 4.81 Area %:—98.99 (Max), 99.59 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 8.92 (s, 1H), 7.75 (dd, J=1.96,8.28 Hz, 1H), 7.32 (t, J=8.32 Hz, 2H), 7.25 (t, J=7.64 Hz, 2H), 7.15 (d,J=7.64 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 3.46-3.39 (m, 6H), 3.22-3.21 (m,8H), 2.60 (s, 3H), 2.45 (t, J=8.04 Hz, 2H), 2.39 (s, 3H), 2.11-2.0 (m,2H), 1.86-1.79 (m, 2H).

5-Ethyl-oxazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 51.5%.

Color and appearance: Off white solid.

LCMS: Mass found (M+559.3).

Rt (min): 4.38 Area %:—93.67 (Max), 97.04 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.9 (s, 1H), 8.9 (s, 1H), 7.76 (s, 1H),7.73-7.71 (m, 1H), 7.48 (t, J=5.92 Hz, 1H), 7.29-7.21 (m, 3H), 7.16 (d,J=7.64 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 3.45-3.3.40 (m, 6H), 3.24-3.18(m, 10H), 2.46 (t, J=7.96 Hz, 2H), 2.36 (s, 3H), 2.09-2.03 (m, 2H), 1.84(m, 2H), 1.32 (t, J=7.56 Hz, 3H).

5-Methyl-oxazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 27.7%.

Color and appearance: White solid.

LCMS: Mass found (M+545.3).

Rt (min): 4.04 Area %:—91.51 (Max), 97.19 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 8.92 (s, 1H), 7.75 (s, 1H),7.74-7.72 (m, 2H), 7.59 (t, J=6.0 Hz, 2H), 7.30 (t, J=8.48 Hz, 2H), 7.08(t, J=7.2 Hz, 1H), 3.45-3.40 (m, 6H), 3.25-3.31 (m, 8H), 2.74 (s, 3H),2.47-2.40 (m, 5H), 2.11-2.05 (m, 2H), 1.84-1.80 (s, 2H).

2-Ethyl-oxazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 39.2%.

Color and appearance: White solid.

LCMS: Mass found (M+559.3).

Rt (min): 4.42 Area %:—93.72 (Max), 96.42 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 10.00 (s, 1H), 9.00 (s, 1H), 8.20 (s, 1H),7.75 (dd, J=2.04, 8.24 Hz, 1H), 7.60 (s, 1H), 7.24 (d, J=2.72 Hz, 1H),7.21-7.19 (m, 2H), 7.13 (d, J=7.6 Hz, 1H), 7.06 (t, J=7.32 Hz, 1H),3.45-3.40 (m, 6H), 3.21-3.12 (m, 8H), 2.87-2.81 (m, 2H), 2.48 (t, J=7.92Hz, 2H), 2.38 (s, 3H), 2.09-2.05 (m, 2H), 1.83 (t, J=6.44 Hz, 2H), 1.44(t, J=7.56 Hz, 3H).

3-Methyl-isoxazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 18.5%.

Color and appearance: White solid.

LCMS: Mass found (M+545.3).

Rt (min): 3.78 Area %:—96.87 (Max), 98.58 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.89 (s, 1H), 8.84 (s, 1H), 7.76(dd, J=1.88, 8.24 Hz, 1H), 7.66 (s, 1H), 7.38 (d, J=8.32 Hz, 1H), 7.24(t, J=3.96 Hz, 2H), 7.09-7.03 (m, 2H), 3.45-3.40 (m, 6H), 3.09 (m, 8H),2.65 (s, 3H), 2.48 (t, J=7.96 Hz, 2H), 2.36 (s, 3H), 2.12-2.04 (m, 2H),1.84-1.78 (m, 2H).

5-Ethyl-3-methyl-isoxazole-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 13.8%.

Color and appearance: White solid.

LCMS: Mass found (M+573.3).

Rt (min): 4.41 Area %:—95.41 (Max), 97.34 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.90 (s, 1H), 7.75 (dd, J=2.0,8.32 Hz, 1H), 7.68 (s, 1H) 7.43 (d, J=8.28 Hz, 1H), 7.23 (t, J=7.2 Hz,2H), 7.07 t, J=7.92 Hz, 2H), 3.46-3.42 (m, 6H), 3.09 (m, 8H), 3.06-3.04(m, 2H), 2.75 (s, 3H), 2.47 (t, J=8.0 Hz, 2H), 2.36 (s, 3H), 2.08-2.04(m, 2H), 1.85-1.81 (m, 2H), 1.42 (t, J=4.56 Hz, 3H).

3-(Cyclohexanecarbonyl-amino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 64.9%.

Color and appearance: Brown solid.

LCMS: Mass found (M+546.3).

Rt (min): 4.56 Area %:—95.44 (Max), 95.51 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 8.8 (s, 1H), 8.6 (s, 1H), 7.70 (dd, J=1.96,8.24 Hz, 1H), 7.43 (s, 1H), 7.24 (m, 1H), 7.22 (t, J=6.16 Hz, 2H), 7.11(d, J=7.48 Hz, 1H), 7.06 (t, J=7.36 Hz, 1H), 3.44-3.38 (m, 6H),3.11-3.07 (m, 8H), 2.45 (t, J=8.0 Hz, 2H), 2.36 (s, 3H), 2.34 (m, 1H),2.08-2.06 (m, 4H), 2.04-2.00 (m, 1H), 1.88-1.80 (m, 3H), 1.57-1.53 (m,2H), 1.38-1.25 (m, 4H).

Tetrahydro-furan-2-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 75.8%.

Color and appearance: White solid.

LCMS: Mass found (M+534.3).

Rt (min): 3.98 Area %:—98.49 (Max), 98.11 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.6 (s, 1H), 8.91 (s, 1H), 7.72 (dd, J=2.0,8.28 Hz, 1H), 7.55 (s, 1H), 7.26-7.20 (m, 3H), 7.13 (d, J=7.12 Hz, 1H),7.06 (t, J=7.32 Hz, 1H), 4.55-4.51 (m, 1H), 4.10-4.08 (m, 1H), 4.00-3.98(m, 1H), 3.44-3.41 (m, 6H), 3.18-3.04 (m, 8H), 2.46 (m, 3H), 2.37 (s,3H), 2.08-2.05 (m, 1H), 1.97-1.94 (m, 2H), 1.83-1.82 (m, 2H), 1.80-1.79(m, 2H).

1-Methyl-piperidine-4-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 19.7%.

Color and appearance: Brown gum.

LCMS: Mass found (M+561.3).

Rt (min): 2.85 Area %:—95.09 (Max), 97.27 (254 nm).

¹H NMR (400 MHz, MeOD) δ 8.31 (s, 1H), 7.66 (dd, J=2.08, 8.32 Hz, 1H),7.33 (d, J=8.4 Hz, 1H), 7.19-7.14 (m, 3H), 6.98 (t, J=1.6 Hz, 1H), 3.52(t, J=7.08 Hz, 2H), 3.48-3.38 (m, 4H), 3.10 (m, 8H), 3.32-3.31 (m, 2H),3.01-2.98 (m, 1H), 2.42-2.38 (m, 2H), 2.34-3.32 (m, 3H), 2.17 (s, 3H),2.08-2.04 (m, 2H), 1.91-1.90 (m, 2H), 1.88-1.87 (m, 2H), 1.85-1.83 (m,4H).

3-(Cyclopropanecarbonyl-amino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 67.4%.

Color and appearance: White solid.

LCMS: Mass found (M+504.3).

Rt (min): 3.56 Area %:—95.97 (Max), 97.03 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 8.63 (s, 1H), 7.70 (dd, J=2.04,8.24 Hz, 1H), 7.42 (s, 1H), 7.29 (s, 1H), 7.23 (t, J=7.68 Hz, 2H), 7.12(d, J=7.8 Hz, 1H), 7.05 (t, J=7.36 Hz, 1H), 3.37 (m, 6H), 3.2 (m, 8H),2.42 (m, 2H), 2.3 (s, 3H), 2.05-2.02 (m, 2H), 1.83-1.81 (m, 2H),1.78-1.76 (m, 1H), 1.15-1.11 (m, 2H), 0.98-0.86 (m, 2H).

3-(2-Chloro-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 51.7%.

Color and appearance: Brown solid.

LCMS: Mass found (M+574.3).

Rt (min): 4.28 Area %:—93.60 (Max), 96.10 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 9.06 (s, 1H), 7.84 (d, J=6.96Hz, 1H), 7.77 (dd, J=1.68, 8.24 Hz, 1H), 7.58 (s, 1H), 7.49-7.46 (m,1H), 7.44-7.38 (m, 3H), 7.23 (t, J=7.84 Hz, 2H), 7.19 (m, 2H), 3.46-3.42(m, 6H), 3.19 (m, 8H), 2.47-2.42 (m, 5H), 2.10-2.06 (m, 2H), 1.84-1.79(m, 2H).

3-(2-Fluoro-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 36.7%.

Color and appearance: Brown solid.

LCMS: Mass found (M+558.3).

Rt (min): 4.39 Area %:—96.46 (Max), 96.94 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 9.09 (s, 1H), 8.29 (t, J=6.4 Hz,1H), 7.78 (dd, J=2.08, 8.28 Hz, 1H), 7.68 (m, 1H), 7.54-7.52 (m, 1H),7.40 (d, J=8.28 Hz, 1H), 7.36 (t, J=6.92 Hz, 1H), 7.32 (m, 4H), 7.13 (t,J=4.24 Hz, 1H), 3.46-3.42 (m, 6H), 3.28 (m, 8H), 2.48-2.43 (m, 5H),2.10-2.06 (m, 2H), 1.85-1.82 (m, 2H).

3-(3-Dimethylamino-benzoylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide

Yield: 45.3%.

Color and appearance: Brown gum.

LCMS: Mass found (M+583.3).

Rt (min): 3.73 Area %:—92.47 (Max), 94.61 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.41 (s, 1H), 9.04 (s, 1H), 7.76 (dd, J=1.84,8.24 Hz, 1H), 7.59 (s, 1H), 7.41-7.33 (m, 3H), 7.23 (t, J=7.28 Hz, 3H),7.07 (m, 2H), 6.92 (s, 1H), 3.46-3.42 (m, 6H), 3.12-3.05 (m, 8H), 3.01(s, 6H), 2.47 (t, J=7.88 Hz, 2H), 2.36 (s, 3H), 2.11-2.03 (m, 2H),1.86-1.80 (m, 2H).

N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-3-(2-trifluoromethyl-benzoylamino)-benzamide

Yield: 32.3%.

Color and appearance: Brown solid.

LCMS: Mass found (M+608.3).

Rt (min): 4.49 Area %:—95.91 (Max), 97.61 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 2H), 7.79 (t, J=7.6 Hz, 2H),7.69-7.62 (m, 3H), 7.53 (s, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.22-7.15 (m,2H), 7.05 (t, J=7.72 Hz, 2H), 3.46-3.42 (m, 6H), 3.13-3.04 (m, 8H), 2.46(t, J=8.0 Hz, 2H), 2.36 (s, 3H), 2.11-2.04 (m, 2H), 1.85-1.80 (m, 2H).

Naphthalene-1-carboxylic acid[5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 10.9%.

Color and appearance: Brown gum.

LCMS: Mass found (M+590.3).

Rt (min): 4.70 Area %:—90.60 (Max), 91.80 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.1 (s, 2H), 8.52 (d, J=8.92 Hz, 1H), 7.99 (d,J=8.2 Hz, 1H), 7.94 (d, J=7.28 Hz, 1H), 7.80 (t, J=6.72 Hz, 2H), 7.60(s, 1H), 7.59-7.55 (m, 3H), 7.38 (d, J=8.28 Hz, 1H), 7.20-7.15 (m, 2H),7.04 (t, J=7.28 Hz, 1H), 6.96 (d, J=8.08 Hz, 1H), 3.47-3.44 (m, 6H),3.16-3.10 (m, 8H), 2.48 (t, J=8.0 Hz, 2H), 2.35 (s, 3H), 2.10-2.06 (m,2H), 1.87-1.84 (m, 2H).

Furan-2-carboxylic acid[5-(3-phenyl-propylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

To a suspension of3-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid(0.1 g, 0.246 mmol) in methylene dichloride (5 ml), triethylamine (0.074g, 0.74 mmol), (3-phenylpropyl)amine (0.044 g, 0.370 mmol) and 1-propanephosphonic cyclic anhydride (0.23 g, 0.74 mmol) were added. The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas concentrated and extracted with dichloromethane (10 ml×1). Theorganic layer was washed with water (10 ml×2) and dried over anhydroussodium sulfate. The organic layer was concentrated and the crude productobtained was purified by flash chromatography using silica gel column toget (0.070 g, 67.9%) of the titled compound as a brown solid.

LCMS: Mass found (M+523.3).

Rt (min): 5.42 Area %:—90.74 (Max), 92.59 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.5 (s, 1H), 8.80 (s, 1H), 7.75 (dd, J=2.08,8.28 Hz, 1H), 7.58 (s, 1H), 7.34 (d, J=8.32 Hz, 2H), 7.30-7.25 (m, 7H),7.14 (d, J=8.08 Hz, 1H), 7.05 (m, 1H), 6.61 (s, 1H), 6.60 (s, 1H), 3.51(m, 2H), 3.18-3.12 (m, 8H), 2.75 (t, J=7.44 Hz, 2H), 2.37 (s, 3H),1.99-96 (m, 2H).

HPLC: Rt (min) 5.46 Area %:—92.64 (Max), 94.27 (254 nm).

Furan-2-carboxylic acid[5-(3-pyrazol-1-yl-propylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 64.4%.

Color and appearance: Yellow solid.

LCMS: Mass found (M+513.3).

Rt (min): 4.49 Area %:—99.33 (Max), 99.86 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 9.5 (s, 1H), 8.85 (s, 1H), 7.76 (dd, J=2.12,8.28 Hz, 1H), 7.58 (s, 2H), 7.57 (s, 1H), 7.34 (d, J=8.28 Hz, 1H),7.29-7.28 (m, 3H), 7.25-7.2481 (m, 2H), 7.23 (m, 1H), 6.60 (s, 1H), 6.27(s, 1H), 4.30 (t, J=6.4 Hz, 2H), 2.48-2.46 (m, 2H), 3.19-3.13 (m, 8H),2.37 (s, 3H), 2.18-1.76 (m, 2H).

Furan-2-carboxylic acid[5-(1-cyclopentylcarbamoyl-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide

Yield: 48.4%.

Color and appearance: Brown solid.

LCMS: Mass found (M+544.3).

Rt (min): 4.72 Area %:—90.79 (Max), 90.20 (254 nm).

¹H NMR (400 MHz, CDCl₃) δ 95 (s, 1H), 8.88 (s, 1H), 7.69 (dd, J=2.04,8.24 Hz, 1H), 7.57 (s, 1H), 7.34 (d, J=8.28 Hz, 1H), 7.29-7.28 (m, 3H),7.25 (d, J=7.08 Hz, 1H), 7.18 (m, 1H), 7.09 (d, J=7.36 Hz, 1H), 6.85 (d,J=7.48 Hz, 1H), 6.61 (m, 1H), 4.64 (m, 1H), 4.20-4.18 (m, 1H), 3.21-3.18(m, 8H), 2.40 (s, 3H), 1.98-1.97 (m, 2H), 1.69-1.67 (m, 2H), 1.65-1.58(m, 2H), 1.49-1.48 (m, 3H), 1.44-1.40 (m, 2H).

Example 10

EC₅₀ of cyclic AMP production in CHO FSHR cells+EC₂₀ FSH (Assay A) 2500Cho-FSHR-LUC-1-1-43 cells were plated per well in 5 μl of phenol redfree DMEM/F12+1% FBS. Cells were plated in 384 well, solid white lowvolume plates (Greiner 784075) by Multidrop. Cells were assayed byadding 100 μl of 2×EC₂₀ FSH/IBMX in DMEM/F12+0.1% BSA) by Multidrop to 2μl of test compound stamped in 384 well plates (compounds are diluted1:50). The final FSH concentration was 0.265 μM, and the final IBMXconcentration was 200 μM. The compound plate map was as follows: Column1: 2 μl of DMSO; Column 2: 2 μl of DMSO; Columns 3-12 and 13-24: 2 μl oftest compound, diluted 1:4 in 100% DMSO, or 2 μl of FSH, diluted 1:4 inDMEM/F12+0.1% BSA. The starting concentration for FSH was 50 nM (finalconcentration was 0.5 nM). Furthermore, Column 23 contained 2 μl of EC₁₀FSH reference (100×) (diluted in DMEM/F12+0.1% BSA) at a finalconcentration of 0.5 nM, and Column 24 contained 2 μl of 1 mM AS707664/2reference compound 2. 5 μl of compound+EC₂₀ FSH mixture were transferredto cell plates (1:2 dilution into 5 μl of cell media) The plates wereincubated at 37° C. for 1 h. 10 μl of mixed HTRF (CisBio #62AM4PEC)reagents were added per well and incubated at room temperature for 1 h.The plates were read on Envision using the cAMP HTRF—low volume 384 wellprotocol. The readout was the calculated fluorescence ratio (665 nm/620nm). Values given in percent (%) indicate the percental effect(response) at a certain concentration of agonist relative to the maximumresponse of the FSH standard. Results are given in Table 1 and 2.

Example 11 Rat Granulosa EC₅₀ FSH (Assay B)

The assay was performed pursuant to the teaching of Yanofsky et al.(2006) Allosteric activation of the follicle-stimulating hormone (FSH)receptor by selective, nonpeptide agonists. JBC 281(19): 13226-13233,which is incorporated by reference in the disclosure of the invention.Results are given in Table 1 and 2.

Example 12 Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water was adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, lyophilized understerile conditions and sealed under sterile conditions. Each injectionvial contained 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention was melted with 100 g of soy lecithin and 1400 g ofcocoa butter, poured into moulds and allowed to cool. Each suppositorycontained 20 mg of active ingredient.

(C) Solution: A solution was prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH was adjusted to 6.8, and the solution was madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionwere mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate was pressed to give tablets in aconventional manner in such a way that each tablet contained 10 mg ofactive ingredient.

(F) Coated tablets: Tablets were pressed analogously to Example E andsubsequently coated in a conventional manner with a coating of sucrose,potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionwere introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contained 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water was sterile filtered,transferred into ampoules, lyophilized under sterile conditions andsealed under sterile conditions. Each ampoule contained 10 mg of activeingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention were dissolved in 10 I of isotonic NaCl solution, and thesolution was transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponded to a dose of about 0.14mg.

1. A compound of formula (I)

wherein W¹, W² denote independently from one another N or CR⁸, whereinone of W¹ or W² denotes N; R¹ denotes —(CY₂)_(n)-E-(CY₂)_(n)-Het³,—(CY₂)_(n)-Cyc-Het³, —(CY₂)_(n)—NY-Het³, —(CY₂)_(n)—CONH-Het³,—(CY₂)_(n)—NHCO-Het³, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)-Het³,(CY₂)_(n)-Het¹, —(CY₂)_(n)—CONH-Het¹, —(CY₂)_(n)—NHCO-Het¹,—(CY₂)_(n)—Ar, -Cyc-Ar, —(CY₂)_(n)—NY—Ar, —(CY₂)_(n)—CONH—Ar,—(CY₂)_(n)—NHCO—Ar, —(CY₂)_(n)—C(Y)(OH)—(CY₂)_(n)—Ar, —(CY₂)_(n)-Cyc,—(CY₂)_(n)—NY-Cyc, —(CY₂)_(n)—CONH-Cyc, —(CY₂)_(n)—NHCO-Cyc,—(CY₂)_(n)—NHCO—NH-Cyc, Y, —(CYR⁸)_(n)—OY, —(CY₂)_(n)—COOY,—(CY₂)_(n)—SO₂Y, —(CYR⁸)_(n)—CO—(CY₂)_(n)—N(R⁸)₂,—(CY₂)_(n)—[C(Y)(OH)]_(m)—(CYR⁸)_(n)—NY₂,[—(CY₂)_(n)—O]_(m)—(CYR⁸)_(n)—NYCOY, —(CY₂)_(n)—NYCOOY,—(CY₂)_(n)—NYSO₂Y, —(CY₂)_(n)—NYCON(R⁸)₂, —(CY₂)_(n)—NHCO—CH═CH₂,—(CY₂)_(n)—NHCO—NH—(CY₂)_(n)═CH₂ or —(CY₂)_(n)—CN; R² denotes Y; or R¹,R² together denote —(CY₂)_(p)—NH—(CY₂)—, —(CY₂)_(p)—NHCO—(CY₂)_(p)—,—(CY₂)_(p)—CONH—(CY₂)_(p)—, —(CY₂)_(p)—N(COA)-(CY₂)_(p)—,—(CY₂)_(p)—N(COOA)-(CY₂)_(p)—, —(CY₂)_(p)—C(Y)(Het³)-(CY₂)_(p)—,

R³ denotes —(CY₂)_(n)-Het¹, —(CY₂)_(n)-Het³, —(CY₂)_(n)—Ar,—C(Y)(OY)—Ar, Y or —(CY₂)_(n)-Cyc; R⁴ denotes Y, COY or SO₂Y; R⁵ denotesE-Ar, NY—Ar, Cyc, Y, OY, NYY, NYCOOY, NYCOY, COY, COOY, SO₂Y, Het¹ orHet³; R⁶, R⁷ together denote —(CY₂)_(p)—; R⁸ denotes Y or Ar; X, E eachindependently is —(CY₂)_(m)—, O, CO, —COO— or SO₂; Y denotes H or A; Adenotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7Hatoms can be replaced independently from one another by Hal, ═O and/orOH; Cyc denotes cycloalkyl having 3-7 C atoms, in which 1-4H atoms canbe replaced independently from one another by Hal and/or OH; Ar denotesan unsaturated or aromatic mono- or bicyclic carbocycle having 3-10 Catoms, which can be substituted by at least one substituent selectedfrom the group of A, Hal, —(CY₂)_(n)—OY, COOY, CONH₂, NHCOY,—(CY₂)_(n)—NYCOOY, —(CY₂)_(n)—NY₂, NO₂, SO₂Y, SO₂NY₂, NYSO₂Y,—(CY₂)_(n)—CN, —(CY₂)_(n)-Het² and Cyc, or which can be fused to Cyc;Het¹ denotes an unsaturated or aromatic mono- or bicyclic heterocyclehaving 1-10 C atoms and 1-4 N, O and/or S atoms, which can besubstituted by at least one substituent selected from the group of Hal,A, Cyc, OY, ═O, COOY, CONH₂, NHCOY, —(CY₂)_(n)—NY₂, SO₂Y, SO₂NY₂,NHSO₂Y, CN, Ar and —(CY₂)_(n)-Het³; Het² denotes a saturated orunsaturated monocyclic 5- or 6-membered heterocycle having 1-4 C atomsand 1-4 N, O and/or S atoms, which can be substituted by A and/or ═O;Het³ denotes a saturated mono- or bicyclic heterocycle having 3-7 Catoms and 1-4 N, O and/or S atoms, which can be substituted by at leastone substituent selected from the group of ═O, A, Hal, —(CY₂)_(n)-Cyc,—(CY₂)_(n)—OY, COY, COOY, CONY₂, NHCOY, —(CY₂)_(n)—NY₂, CN, SO₂Y and—(CY₂)_(n)—Ar; Hal denotes F, Cl, Br or I; m, n each independently is 0,1, 2, 3, 4, 5 or 6; and p denotes 1, 2 or 3; or a physiologicallyacceptable salt thereof.
 2. (canceled)
 3. The compound according toclaim 1, wherein X denotes CO.
 4. The compound according to claim 1,wherein R¹, R³, each independently is —(CY₂)_(n)-Het³, —(CY₂)_(n)-Het¹,—(CY₂)_(n)—Ar or Cyc.
 5. The compound according to claim 1, wherein R²,R⁴, R⁸ denote H. 6-9. (canceled)
 10. A pharmaceutical compositioncomprising at least one compound according to claim 1 or aphysiologically acceptable salt thereof.
 11. The pharmaceuticalcomposition according to claim 10, comprising pharmaceutically tolerableadjuvants for oral administration
 12. The pharmaceutical compositionaccording to claim 10, comprising at least a second activepharmaceutical ingredient.
 13. (canceled)
 14. (canceled)
 15. Thecompound according to claim 1, which is selected from:

or a physiologically acceptable salt thereof.